Pharmaceuticals

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Open AccessEditorial

Special Issue “Anticancer Drugs 2021”

by Mary J. Meegan and Niamh M. O’Boyle

Pharmaceuticals 2022, 15(4), 479; https://doi.org/10.3390/ph15040479 - 14 Apr 2022

Cited by 3 | Viewed by 2597

Abstract

This Special Issue of Pharmaceuticals is devoted to significant advances achieved in the field of Anticancer Drugs in 2021 [...] Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

Research

Jump to: Editorial, Review

15 pages, 1829 KiB

Open AccessArticle

Acquired Drug Resistance Enhances Imidazoquinoline Efflux by P-Glycoprotein

by Anunay J. Pulukuri, Anthony J. Burt, Larissa K. Opp, Colin M. McDowell, Maryam Davaritouchaee, Amy E. Nielsen and Rock J. Mancini

Pharmaceuticals 2021, 14(12), 1292; https://doi.org/10.3390/ph14121292 - 10 Dec 2021

Cited by 3 | Viewed by 3976

Abstract

Multidrug-Resistant (MDR) cancers attenuate chemotherapeutic efficacy through drug efflux, a process that transports drugs from within a cell to the extracellular space via ABC (ATP-Binding Cassette) transporters, including P-glycoprotein 1 (P-gp or ABCB1/MDR1). Conversely, Toll-Like Receptor (TLR) agonist immunotherapies modulate activity of tumor-infiltrating [...] Read more.

Multidrug-Resistant (MDR) cancers attenuate chemotherapeutic efficacy through drug efflux, a process that transports drugs from within a cell to the extracellular space via ABC (ATP-Binding Cassette) transporters, including P-glycoprotein 1 (P-gp or ABCB1/MDR1). Conversely, Toll-Like Receptor (TLR) agonist immunotherapies modulate activity of tumor-infiltrating immune cells in local proximity to cancer cells and could, therefore, benefit from the enhanced drug efflux in MDR cancers. However, the effect of acquired drug resistance on TLR agonist efflux is largely unknown. We begin to address this by investigating P-gp mediated efflux of TLR 7/8 agonists. First, we used functionalized liposomes to determine that imidazoquinoline TLR agonists Imiquimod, Resiquimod, and Gardiquimod are substrates for P-gp. Interestingly, the least potent imidazoquinoline (Imiquimod) was the best P-gp substrate. Next, we compared imidazoquinoline efflux in MDR cancer cell lines with enhanced P-gp expression relative to parent cancer cell lines. Using P-gp competitive substrates and inhibitors, we observed that imidazoquinoline efflux occurs through P-gp and, for Imiquimod, is enhanced as a consequence of acquired drug resistance. This suggests that enhancing efflux susceptibility could be an important consideration in the rational design of next generation immunotherapies that modulate activity of tumor-infiltrating immune cells. Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

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23 pages, 2596 KiB

Open AccessArticle

Discovery of a Novel Template, 7-Substituted 7-Deaza-4′-Thioadenosine Derivatives as Multi-Kinase Inhibitors

by Karishma K. Mashelkar, Woong Sub Byun, Hyejin Ko, Kisu Sung, Sushil K. Tripathi, Seungchan An, Yun A Yum, Jee Youn Kwon, Minjae Kim, Gibae Kim, Eun-Ji Kwon, Hyuk Woo Lee, Minsoo Noh, Sang Kook Lee and Lak Shin Jeong

Pharmaceuticals 2021, 14(12), 1290; https://doi.org/10.3390/ph14121290 - 10 Dec 2021

Cited by 4 | Viewed by 4180

Abstract

The development of anticancer drugs remains challenging owing to the potential for drug resistance. The simultaneous inhibition of multiple targets involved in cancer could overcome resistance, and these agents would exhibit higher potency than single-target inhibitors. Protein kinases represent a promising target for [...] Read more.

The development of anticancer drugs remains challenging owing to the potential for drug resistance. The simultaneous inhibition of multiple targets involved in cancer could overcome resistance, and these agents would exhibit higher potency than single-target inhibitors. Protein kinases represent a promising target for the development of anticancer agents. As most multi-kinase inhibitors are heterocycles occupying only the hinge and hydrophobic region in the ATP binding site, we aimed to design multi-kinase inhibitors that would occupy the ribose pocket, along with the hinge and hydrophobic region, based on ATP-kinase interactions. Herein, we report the discovery of a novel 4′-thionucleoside template as a multi-kinase inhibitor with potent anticancer activity. The in vitro evaluation revealed a lead 1g (7-acetylene-7-deaza-4′-thioadenosine) with potent anticancer activity, and marked inhibition of TRKA, CK1δ, and DYRK1A/1B kinases in the kinome scan assay. We believe that these findings will pave the way for developing anticancer drugs. Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

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23 pages, 4393 KiB

Open AccessArticle

Effect of a Low Dose of Carvedilol on Cyclophosphamide-Induced Urinary Toxicity in Rats—A Comparison with Mesna

by Anna Merwid-Ląd, Piotr Ziółkowski, Marta Szandruk-Bender, Agnieszka Matuszewska, Adam Szeląg and Małgorzata Trocha

Pharmaceuticals 2021, 14(12), 1237; https://doi.org/10.3390/ph14121237 - 29 Nov 2021

Cited by 8 | Viewed by 3063

Abstract

One of the major side effects of cyclophosphamide (CPX)—an alkylating anticancer drug that is still clinically used—is urotoxicity with hemorrhagic cystitis. The present study was designed to evaluate the ability of carvedilol to protect rats from cyclophosphamide-induced urotoxicity. Rats were injected intraperitoneally ( [...] Read more.

One of the major side effects of cyclophosphamide (CPX)—an alkylating anticancer drug that is still clinically used—is urotoxicity with hemorrhagic cystitis. The present study was designed to evaluate the ability of carvedilol to protect rats from cyclophosphamide-induced urotoxicity. Rats were injected intraperitoneally (i.p.) with CPX (200 mg/kg) and administered carvedilol (2 mg/kg) intragastrically a day before, at the day and a day after a single i.p. injection of CPX, with or without mesna (40, 80, and 80 mg/kg i.p. 20 min before, 4 h and 8 h after CPX administration, respectively). Pretreatment with carvedilol partly prevented the CPX-induced increase in urinary bladder and kidney index, and completely protects from CPX-evoked alterations in serum potassium and creatinine level, but did not prevent histological alterations in the urinary bladder and hematuria. However, carvedilol administration resulted in significant restoration of kidney glutathione (GSH) level and a decrease in kidney interleukin 1β (IL-1β) and plasma asymmetric dimethylarginine (ADMA) concentrations. Not only did mesna improve kidney function, but it also completely reversed histological abnormalities in bladders and prevented hematuria. In most cases, no significant interaction of carvedilol with mesna was observed, although the effect of both drugs together was better than mesna given alone regarding plasma ADMA level and kidney IL-1β concentration. In conclusion, carvedilol did not counteract the injury caused in the urinary bladders but restored kidney function, presumably via its antioxidant and anti-inflammatory properties. Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

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21 pages, 4708 KiB

Open AccessArticle

Design, Synthesis, In Vitro Anticancer Evaluation and Molecular Modelling Studies of 3,4,5-Trimethoxyphenyl-Based Derivatives as Dual EGFR/HDAC Hybrid Inhibitors

by Tarek S. Ibrahim, Azizah M. Malebari and Mamdouh F. A. Mohamed

Pharmaceuticals 2021, 14(11), 1177; https://doi.org/10.3390/ph14111177 - 17 Nov 2021

Cited by 15 | Viewed by 3555

Abstract

Recently, combining histone deacetylase (HDAC) inhibitors with chemotherapeutic drugs or agents, in particular epidermal growth factor receptor (EGFR) inhibitors, is considered to be one of the most encouraging strategy to enhance the efficacy of the antineoplastic agents and decrease or avoid drug resistance. [...] Read more.

Recently, combining histone deacetylase (HDAC) inhibitors with chemotherapeutic drugs or agents, in particular epidermal growth factor receptor (EGFR) inhibitors, is considered to be one of the most encouraging strategy to enhance the efficacy of the antineoplastic agents and decrease or avoid drug resistance. Therefore, in this work, based on introducing 3,4,5-trimethoxy phenyl group as a part of the CAP moiety, in addition to incorporating 4–6 aliphatic carbons linker and using COOH or hydroxamic acid as ZBG, 12 novel EGFR/HDAC hybrid inhibitors 2a–c, 3a–c, 4a–c and 5a–c were designed, constructed, and evaluated for their anticancer activities against 4 cancer cell lines (HepG2, MCF-7, HCT116 and A549). Among all, hybrids with hydroxamic acid 4a–c and 5a, exhibited the highest inhibition against all cancer cell lines with IC₅₀ ranging from 0.536 to 4.892 μM compared to Vorinostat (SAHA) with IC₅₀ ranging from 2.43 to 3.63 μM and Gefitinib with IC₅₀ ranging from 1.439 to 3.366 μM. Mechanistically, the most potent hybrids 4a–c and 5a were further tested for their EGFR and HDACs inhibitory activities. The findings disclosed that hybrid 4b displayed IC₅₀ = 0.063 µM on the target EGFR enzyme which is slightly less potent than the standard Staurosporine (IC₅₀ = 0.044 µM). Furthermore, hybrid 4b showed less HDAC inhibitory activity IC₅₀ against HDAC1 (0.148), 2 (0.168), 4 (5.852), 6 (0.06) and 8 (2.257) than SAHA. In addition, the investigation of apoptotic action of the most potent hybrid 4b showed a significant increase in Bax level up to 3.75-folds, with down-regulation in Bcl2 to 0.42-fold, compared to the control. Furthermore, hybrid 4b displayed an increase in the levels of Caspases 3 and 8 by 5.1 and 3.15 folds, respectively. Additionally, the cell cycle analysis of hybrid 4b revealed that it showed programmed cell death and cell cycle arrest at G1/S phase. Moreover, all these outcomes together with the molecular docking study recommended the rationalized target hybrids 4a–c and 5a, particularly 4b, may be considered to be promising lead candidates for discovery of novel anticancer agents via dual inhibition of both EGFR/HDAC enzymes. Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

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14 pages, 2848 KiB

Open AccessArticle

Exploration of Benzenesulfonamide-Bearing Imidazole Derivatives Activity in Triple-Negative Breast Cancer and Melanoma 2D and 3D Cell Cultures

by Benas Balandis, Vytautas Mickevičius and Vilma Petrikaitė

Pharmaceuticals 2021, 14(11), 1158; https://doi.org/10.3390/ph14111158 - 13 Nov 2021

Cited by 15 | Viewed by 2439

Abstract

Heterocyclic compounds are one of the main groups of organic compounds possessing wide range of applications in various areas of science and their derivatives are present in many bioactive structures. They display a wide variety of biological activities. Recently, more and more attention [...] Read more.

Heterocyclic compounds are one of the main groups of organic compounds possessing wide range of applications in various areas of science and their derivatives are present in many bioactive structures. They display a wide variety of biological activities. Recently, more and more attention has been focused to such heterocyclic compounds as azoles. In this work, we have synthesized a series of new imidazole derivatives incorporating a benzenesulfonamide moiety in their structure, which then were evaluated for their cytotoxicity against human triple-negative breast cancer MDA-MB-231 and human malignant melanoma IGR39 cell lines by MTT assay. Benzenesulfonamide-bearing imidazole derivatives containing 4-chloro and 3,4-dichlorosubstituents in benzene ring, and 2-ethylthio and 3-ethyl groups in imidazole ring have been determined as the most active compounds. Half-maximal effective concentration (EC₅₀) of the most cytotoxic compound was 27.8 ± 2.8 µM against IGR39 cell line and 20.5 ± 3.6 µM against MDA-MB-231 cell line. Compounds reduced cell colony formation of both cell lines and inhibited the growth and viability of IGR39 cell spheroids more efficiently compared to triple-negative breast cancer spheroids. Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

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20 pages, 1815 KiB

Open AccessArticle

Inhibition of XPO-1 Mediated Nuclear Export through the Michael-Acceptor Character of Chalcones

by Marta Gargantilla, José López-Fernández, Maria-Jose Camarasa, Leentje Persoons, Dirk Daelemans, Eva-Maria Priego and María-Jesús Pérez-Pérez

Pharmaceuticals 2021, 14(11), 1131; https://doi.org/10.3390/ph14111131 - 6 Nov 2021

Cited by 9 | Viewed by 4174

Abstract

The nuclear export receptor exportin-1 (XPO1, CRM1) mediates the nuclear export of proteins that contain a leucine-rich nuclear export signal (NES) towards the cytoplasm. XPO1 is considered a relevant target in different human diseases, particularly in hematological malignancies, tumor resistance, inflammation, neurodegeneration and [...] Read more.

The nuclear export receptor exportin-1 (XPO1, CRM1) mediates the nuclear export of proteins that contain a leucine-rich nuclear export signal (NES) towards the cytoplasm. XPO1 is considered a relevant target in different human diseases, particularly in hematological malignancies, tumor resistance, inflammation, neurodegeneration and viral infections. Thus, its pharmacological inhibition is of significant therapeutic interest. The best inhibitors described so far (leptomycin B and SINE compounds) interact with XPO1 through a covalent interaction with Cys528 located in the NES-binding cleft of XPO1. Based on the well-established feature of chalcone derivatives to react with thiol groups via hetero-Michael addition reactions, we have synthesized two series of chalcones. Their capacity to react with thiol groups was tested by incubation with GSH to afford the hetero-Michael adducts that evolved backwards to the initial chalcone through a retro-Michael reaction, supporting that the covalent interaction with thiols could be reversible. The chalcone derivatives were evaluated in antiproliferative assays against a panel of cancer cell lines and as XPO1 inhibitors, and a good correlation was observed with the results obtained in both assays. Moreover, no inhibition of the cargo export was observed when the two prototype chalcones 9 and 10 were tested against a XPO1-mutated Jurkat cell line (XPO1C528S), highlighting the importance of the Cys at the NES-binding cleft for inhibition. Finally, their interaction at the molecular level at the NES-binding cleft was studied by applying the computational tool CovDock. Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

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17 pages, 6628 KiB

Open AccessArticle

Investigation of the Mechanisms of Cytotoxic Activity of 1,3-Disubstituted Thiourea Derivatives

by Paulina Strzyga-Łach, Alicja Chrzanowska, Katarzyna Podsadni and Anna Bielenica

Pharmaceuticals 2021, 14(11), 1097; https://doi.org/10.3390/ph14111097 - 28 Oct 2021

Cited by 14 | Viewed by 2164

Abstract

Substituted thiourea derivatives possess confirmed cytotoxic activity towards cancer but also normal cells. To develop new selective antitumor agents, a series of 3-(trifluoromethyl)phenylthiourea analogs were synthesized, and their cytotoxicity was evaluated in vitro against the cell line panel. Compounds 1–5, [...] Read more.

Substituted thiourea derivatives possess confirmed cytotoxic activity towards cancer but also normal cells. To develop new selective antitumor agents, a series of 3-(trifluoromethyl)phenylthiourea analogs were synthesized, and their cytotoxicity was evaluated in vitro against the cell line panel. Compounds 1–5, 8, and 9 were highly cytotoxic against human colon (SW480, SW620) and prostate (PC3) cancer cells, and leukemia K-562 cell lines (IC₅₀ ≤ 10 µM), with favorable selectivity over normal HaCaT cells. The derivatives exerted better growth inhibitory profiles towards selected tumor cells than the reference cisplatin. Compounds incorporating 3,4-dichloro- (2) and 4-CF₃-phenyl (8) substituents displayed the highest activity (IC₅₀ from 1.5 to 8.9 µM). The mechanisms of cytotoxic action of the most effective thioureas 1–3, 8, and 9 were studied, including the trypan blue exclusion test of cell viability, interleukin-6, and apoptosis assessments. Compounds reduced all cancerous cell numbers (especially SW480 and SW620) by 20–93%. Derivatives 2 and 8 diminished the viability of SW620 cells by 45–58%. Thioureas 1, 2, and 8 exerted strong pro-apoptotic activity. Compound 2 induced late apoptosis in both colon cancer cell lines (95–99%) and in K-562 cells (73%). All derivatives acted as inhibitors of IL-6 levels in both SW480 and SW620 cells, decreasing its secretion by 23–63%. Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

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17 pages, 29664 KiB

Open AccessArticle

Synthesis and Cytotoxic Activity of Combretastatin A-4 and 2,3-Diphenyl-2H-indazole Hybrids

by Jaime Pérez-Villanueva, Félix Matadamas-Martínez, Lilián Yépez-Mulia, Vadim Pérez-Koldenkova, Martha Leyte-Lugo, Karen Rodríguez-Villar, Francisco Cortés-Benítez, Ana Perla Macías-Jiménez, Ignacio González-Sánchez, Ariana Romero-Velásquez, Juan Francisco Palacios-Espinosa and Olivia Soria-Arteche

Pharmaceuticals 2021, 14(8), 815; https://doi.org/10.3390/ph14080815 - 19 Aug 2021

Cited by 7 | Viewed by 3133

Abstract

Cancer is the second leading cause of death, after cardiovascular diseases. Different strategies have been developed to treat cancer; however, chemotherapy with cytotoxic agents is still the most widely used treatment approach. Nevertheless, drug resistance to available chemotherapeutic agents is still a serious [...] Read more.

Cancer is the second leading cause of death, after cardiovascular diseases. Different strategies have been developed to treat cancer; however, chemotherapy with cytotoxic agents is still the most widely used treatment approach. Nevertheless, drug resistance to available chemotherapeutic agents is still a serious problem, and the development of new active compounds remains a constant need. Taking advantage of the molecular hybridization approach, in the present work we designed, synthesized, and tested the cytotoxic activity of two hybrid compounds and seven derivatives based on the structure of combretastatin A-4 and 2,3-diphenyl-2H-indazole. Practical modifications of reported synthetic protocols for 2-pheny-2H-indazole and 2,3-dipheny-2H-indazole derivatives under microwave irradiation were implemented. The cytotoxicity assays showed that our designed hybrid compounds possess strong activity, especially compound 5, which resulted even better than the reference drug cisplatin against HeLa and SK-LU-1 cells (IC₅₀ of 0.16 and 6.63 µM, respectively), and it had similar potency to the reference drug imatinib against K562 cells. Additionally, in silico and in vitro studies strongly suggest tubulin as the molecular target for hybrid compound 5. Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

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20 pages, 3859 KiB

Open AccessArticle

Repurposing FDA Drug Compounds against Breast Cancer by Targeting EGFR/HER2

by Irving Balbuena-Rebolledo, Itzia Irene Padilla-Martínez, Martha Cecilia Rosales-Hernández and Martiniano Bello

Pharmaceuticals 2021, 14(8), 791; https://doi.org/10.3390/ph14080791 - 12 Aug 2021

Cited by 11 | Viewed by 3959

Abstract

Repurposing studies have identified several FDA-approved compounds as potential inhibitors of the intracellular domain of epidermal growth factor receptor 1 (EGFR) and human epidermal receptor 2 (HER2). EGFR and HER2 represent important targets for the design of new drugs against different types of [...] Read more.

Repurposing studies have identified several FDA-approved compounds as potential inhibitors of the intracellular domain of epidermal growth factor receptor 1 (EGFR) and human epidermal receptor 2 (HER2). EGFR and HER2 represent important targets for the design of new drugs against different types of cancer, and recently, differences in affinity depending on active or inactive states of EGFR or HER2 have been identified. In this study, we first identified FDA-approved compounds with similar structures in the DrugBank to lapatinib and gefitinib, two known inhibitors of EGFR and HER2. The selected compounds were submitted to docking and molecular dynamics MD simulations with the molecular mechanics generalized Born surface area approach to discover the conformational and thermodynamic basis for the recognition of these compounds on EGFR and HER2. These theoretical studies showed that compounds reached the ligand-binding site of EGFR and HER2, and some of the repurposed compounds did not interact with residues involved in drug resistance. An in vitro assay performed on two different breast cancer cell lines, MCF-7, and MDA-MB-23, showed growth inhibitory activity for these repurposed compounds on tumorigenic cells at micromolar concentrations. These repurposed compounds open up the possibility of generating new anticancer treatments by targeting HER2 and EGFR. Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

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27 pages, 15083 KiB

Open AccessArticle

Inflammation as a Possible Trigger for Mitoxantrone-Induced Cardiotoxicity: An In Vivo Study in Adult and Infant Mice

by Ana Reis-Mendes, José Luís Dores-Sousa, Ana Isabel Padrão, Margarida Duarte-Araújo, José Alberto Duarte, Vítor Seabra, Salomé Gonçalves-Monteiro, Fernando Remião, Félix Carvalho, Emília Sousa, Maria Lourdes Bastos and Vera Marisa Costa

Pharmaceuticals 2021, 14(6), 510; https://doi.org/10.3390/ph14060510 - 26 May 2021

Cited by 16 | Viewed by 4165

Abstract

Mitoxantrone (MTX) is a pharmaceutical drug used in the treatment of several cancers and refractory multiple sclerosis (MS). Despite its therapeutic value, adverse effects may be severe, namely the frequently reported cardiotoxicity, whose mechanisms need further research. This work aimed to assess if [...] Read more.

Mitoxantrone (MTX) is a pharmaceutical drug used in the treatment of several cancers and refractory multiple sclerosis (MS). Despite its therapeutic value, adverse effects may be severe, namely the frequently reported cardiotoxicity, whose mechanisms need further research. This work aimed to assess if inflammation or oxidative stress-related pathways participate in the cardiotoxicity of MTX, using the mouse as an animal model, at two different age periods (infant or adult mice) using two therapeutic relevant cumulative doses. Histopathology findings showed that MTX caused higher cardiac toxicity in adults. In MTX-treated adults, at the highest dose, noradrenaline cardiac levels decreased, whereas at the lowest cumulative dose, protein carbonylation increased and the expression of nuclear factor kappa B (NF-κB) p65 subunit and of M1 macrophage marker increased. Moreover, MTX-treated adult mice had enhanced expression of NF-κB p52 and tumour necrosis factor (TNF-α), while decreasing interleukin-6 (IL-6). Moreover, while catalase expression significantly increased in both adult and infant mice treated with the lowest MTX cumulative dose, the expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and glutathione peroxidase only significantly increased in infant animals. Nevertheless, the ratio of GAPDH to ATP synthase subunit beta decreased in adult animals. In conclusion, clinically relevant doses of MTX caused dissimilar responses in adult and infant mice, being that inflammation may be an important trigger to MTX-induced cardiotoxicity. Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

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15 pages, 9843 KiB

Open AccessArticle

Synthesis and Anticancer Evaluation of New 1,3,4-Oxadiazole Derivatives

by Camelia Elena Stecoza, George Mihai Nitulescu, Constantin Draghici, Miron Teodor Caproiu, Octavian Tudorel Olaru, Marinela Bostan and Mirela Mihaila

Pharmaceuticals 2021, 14(5), 438; https://doi.org/10.3390/ph14050438 - 6 May 2021

Cited by 41 | Viewed by 4766

Abstract

In order to develop novel chemotherapeutic agents with potent anticancer activities, a series of new 2,5-diaryl/heteroaryl-1,3,4-oxadiazoles were designed and synthesized. The structures of the new compounds were established using elemental analyses, IR and NMR spectral data. The compounds were evaluated for their anticancer [...] Read more.

In order to develop novel chemotherapeutic agents with potent anticancer activities, a series of new 2,5-diaryl/heteroaryl-1,3,4-oxadiazoles were designed and synthesized. The structures of the new compounds were established using elemental analyses, IR and NMR spectral data. The compounds were evaluated for their anticancer potential on two standardized human cell lines, HT-29 (colon adenocarcinoma) and MDA-MB-231 (breast adenocarcinoma). Cytotoxicity was measured by MTS assay, while cell cycle arrest and apoptosis assays were conducted using a flow cytometer, the results showing that the cell line MDA-MB-231 is more sensitive to the compounds’ action. The results of the predictive studies using the PASS application and the structural similarity analysis indicated STAT3 and miR-21 as the most probable pharmacological targets for the new compounds. The promising effect of compound 3e, 2-[2-(phenylsulfanylmethyl)phenyl]-5-(4-pyridyl)-1,3,4-oxadiazole, especially on the MDA-MB-231 cell line motivates future studies to improve the anticancer profile and to reduce the toxicological risks. It is worth noting that 3e produced a low toxic effect in the D. magna 24 h assay and the predictive studies on rat acute toxicity suggest a low degree of toxic risks. Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

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17 pages, 4498 KiB

Open AccessArticle

Design, Synthesis, and Molecular Docking Study of New Tyrosyl-DNA Phosphodiesterase 1 (TDP1) Inhibitors Combining Resin Acids and Adamantane Moieties

by Kseniya Kovaleva, Olga Yarovaya, Konstantin Ponomarev, Sergey Cheresiz, Amirhossein Azimirad, Irina Chernyshova, Alexandra Zakharenko, Vasily Konev, Tatiana Khlebnikova, Evgenii Mozhaytsev, Evgenii Suslov, Dmitry Nilov, Vytas Švedas, Andrey Pokrovsky, Olga Lavrik and Nariman Salakhutdinov

Pharmaceuticals 2021, 14(5), 422; https://doi.org/10.3390/ph14050422 - 1 May 2021

Cited by 11 | Viewed by 3633

Abstract

In this paper, a series of novel abietyl and dehydroabietyl ureas, thioureas, amides, and thioamides bearing adamantane moieties were designed, synthesized, and evaluated for their inhibitory activities against tyrosil-DNA-phosphodiesterase 1 (TDP1). The synthesized compounds were able to inhibit TDP1 at micromolar concentrations (0.19–2.3 [...] Read more.

In this paper, a series of novel abietyl and dehydroabietyl ureas, thioureas, amides, and thioamides bearing adamantane moieties were designed, synthesized, and evaluated for their inhibitory activities against tyrosil-DNA-phosphodiesterase 1 (TDP1). The synthesized compounds were able to inhibit TDP1 at micromolar concentrations (0.19–2.3 µM) and demonstrated low cytotoxicity in the T98G glioma cell line. The effect of the terpene fragment, the linker structure, and the adamantane residue on the biological properties of the new compounds was investigated. Based on molecular docking results, we suppose that adamantane derivatives of resin acids bind to the TDP1 covalent intermediate, forming a hydrogen bond with Ser463 and hydrophobic contacts with the Phe259 and Trp590 residues and the oligonucleotide fragment of the substrate. Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

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12 pages, 1343 KiB

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Mechanistic Modelling Identifies and Addresses the Risks of Empiric Concentration-Guided Sorafenib Dosing

by Warit Ruanglertboon, Michael J. Sorich, Ashley M. Hopkins and Andrew Rowland

Pharmaceuticals 2021, 14(5), 389; https://doi.org/10.3390/ph14050389 - 21 Apr 2021

Cited by 7 | Viewed by 2414

Abstract

The primary objective of this study is to evaluate the capacity of concentration-guided sorafenib dosing protocols to increase the proportion of patients that achieve a sorafenib maximal concentration (C_max) within the range 4.78 to 5.78 μg/mL. A full physiologically based pharmacokinetic [...] Read more.

The primary objective of this study is to evaluate the capacity of concentration-guided sorafenib dosing protocols to increase the proportion of patients that achieve a sorafenib maximal concentration (C_max) within the range 4.78 to 5.78 μg/mL. A full physiologically based pharmacokinetic model was built and validated using Simcyp^® (version 19.1). The model was used to simulate sorafenib exposure in 1000 Sim-Cancer subjects over 14 days. The capacity of concentration-guided sorafenib dose adjustment, with/without model-informed dose selection (MIDS), to achieve a sorafenib C_max within the range 4.78 to 5.78 μg/mL was evaluated in 500 Sim-Cancer subjects. A multivariable linear regression model incorporating hepatic cytochrome P450 (CYP) 3A4 abundance, albumin concentration, body mass index, body surface area, sex and weight provided robust prediction of steady-state sorafenib C_max (R² = 0.883; p < 0.001). These covariates identified subjects at risk of failing to achieve a sorafenib C_max ≥ 4.78 μg/mL with 95.0% specificity and 95.2% sensitivity. Concentration-guided sorafenib dosing with MIDS achieved a sorafenib C_max within the range 4.78 to 5.78 μg/mL for 38 of 52 patients who failed to achieve a C_max ≥ 4.78 μg/mL with standard dosing. In a simulation setting, concentration-guided dosing with MIDS was the quickest and most effective approach to achieve a sorafenib C_max within a designated range. Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

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20 pages, 3391 KiB

Open AccessArticle

Tryptophanol-Derived Oxazolopyrrolidone Lactams as Potential Anticancer Agents against Gastric Adenocarcinoma

by Margarida Espadinha, Valentina Barcherini, Lídia M. Gonçalves, Elies Molins, Alexandra M. M. Antunes and Maria M. M. Santos

Pharmaceuticals 2021, 14(3), 208; https://doi.org/10.3390/ph14030208 - 2 Mar 2021

Cited by 4 | Viewed by 2262

Abstract

Gastric cancer is one of the deadliest cancers in modern societies, so there is a high level of interest in discovering new drugs for this malignancy. Previously, we demonstrated the ability of tryptophanol-derived polycyclic compounds to activate the tumor suppressor protein p53, a [...] Read more.

Gastric cancer is one of the deadliest cancers in modern societies, so there is a high level of interest in discovering new drugs for this malignancy. Previously, we demonstrated the ability of tryptophanol-derived polycyclic compounds to activate the tumor suppressor protein p53, a relevant therapeutic target in cancer. In this work, we developed a novel series of enantiomerically pure tryptophanol-derived small molecules to target human gastric adenocarcinoma (AGS) cells. From an initial screening of fourteen compounds in AGS cell line, a hit compound was selected for optimization, leading to two derivatives selective for AGS gastric cells over other types of cancer cells (MDA-MB-231, A-549, DU-145, and MG-63). More importantly, the compounds were non-toxic in normal cells (HEK 293T). Additionally, we show that the growth inhibition of AGS cells induced by these compounds is mediated by apoptosis. Stability studies in human plasma and human liver microsomes indicate that the compounds are stable, and that the major metabolic transformations of these molecules are mono- and di-hydroxylation of the indole ring. Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

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11 pages, 2316 KiB

Open AccessArticle

Morin-5′-Sulfonic Acid Sodium Salt (NaMSA) Attenuates Cyclophosphamide-Induced Histological Changes in Genitourinary Tract in Rats—Short Report

by Anna Merwid-Ląd, Dorota Ksiądzyna, Agnieszka Hałoń, Danuta Szkudlarek, Małgorzata Trocha, Marta Szandruk-Bender, Agnieszka Matuszewska, Beata Nowak, Tomasz Sozański, Anna Kuźniar and Adam Szeląg

Pharmaceuticals 2021, 14(3), 192; https://doi.org/10.3390/ph14030192 - 26 Feb 2021

Cited by 7 | Viewed by 2061

Abstract

Cyclophosphamide (CPX) exerts toxicity in the urogenital system. The current study was designed to evaluate the effect of morin-5′-sulfonic acid sodium salt (NaMSA) on CPX-induced urogenital toxicity in rats. NaMSA (100 mg/kg/daily) and CPX (15 mg/kg/daily) alone or in combination and 0.9% NaCl [...] Read more.

Cyclophosphamide (CPX) exerts toxicity in the urogenital system. The current study was designed to evaluate the effect of morin-5′-sulfonic acid sodium salt (NaMSA) on CPX-induced urogenital toxicity in rats. NaMSA (100 mg/kg/daily) and CPX (15 mg/kg/daily) alone or in combination and 0.9% NaCl (as a control) were given intragastrically for 10 days. Testes and epididymes from male and urinary bladders from male and female rats were evaluated histologically. In testes and epididymes, morphological changes and relative decrease in sperm count were assessed. In urinary bladders edema, hemorrhage and urothelium erosions were described by 0–2 points scoring system. Reproductive score (RS—in total 6 points) and urinary bladder score (BS—in total 6 points) were thereafter calculated. In CPX-receiving group RS (2.7) and BS (3.3) were significantly higher than in the control (0.5 and 0.25 for RS and BS, respectively). Co-administration of NaMSA reversed most of the morphological changes, which was reflected by lower RS and BS score (0.5 and 1.2 for RS and BS, respectively). The preliminary findings suggest that NaMSA may attenuate CPX-induced histological changes in rat urogenital tract. Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

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54 pages, 14187 KiB

Open AccessArticle

Synthesis and Biological Evaluation of 1-(Diarylmethyl)-1H-1,2,4-triazoles and 1-(Diarylmethyl)-1H-imidazoles as a Novel Class of Anti-Mitotic Agent for Activity in Breast Cancer

by Gloria Ana, Patrick M. Kelly, Azizah M. Malebari, Sara Noorani, Seema M. Nathwani, Brendan Twamley, Darren Fayne, Niamh M. O’Boyle, Daniela M. Zisterer, Elisangela Flavia Pimentel, Denise Coutinho Endringer and Mary J. Meegan

Pharmaceuticals 2021, 14(2), 169; https://doi.org/10.3390/ph14020169 - 22 Feb 2021

Cited by 6 | Viewed by 5438

Abstract

We report the synthesis and biochemical evaluation of compounds that are designed as hybrids of the microtubule targeting benzophenone phenstatin and the aromatase inhibitor letrozole. A preliminary screening in estrogen receptor (ER)-positive MCF-7 breast cancer cells identified 5-((2H-1,2,3-triazol-1-yl)(3,4,5-trimethoxyphenyl)methyl)-2-methoxyphenol 24 as a [...] Read more.

We report the synthesis and biochemical evaluation of compounds that are designed as hybrids of the microtubule targeting benzophenone phenstatin and the aromatase inhibitor letrozole. A preliminary screening in estrogen receptor (ER)-positive MCF-7 breast cancer cells identified 5-((2H-1,2,3-triazol-1-yl)(3,4,5-trimethoxyphenyl)methyl)-2-methoxyphenol 24 as a potent antiproliferative compound with an IC₅₀ value of 52 nM in MCF-7 breast cancer cells (ER+/PR+) and 74 nM in triple-negative MDA-MB-231 breast cancer cells. The compounds demonstrated significant G₂/M phase cell cycle arrest and induction of apoptosis in the MCF-7 cell line, inhibited tubulin polymerisation, and were selective for cancer cells when evaluated in non-tumorigenic MCF-10A breast cells. The immunofluorescence staining of MCF-7 cells confirmed that the compounds targeted tubulin and induced multinucleation, which is a recognised sign of mitotic catastrophe. Computational docking studies of compounds 19e, 21l, and 24 in the colchicine binding site of tubulin indicated potential binding conformations for the compounds. Compounds 19e and 21l were also shown to selectively inhibit aromatase. These compounds are promising candidates for development as antiproliferative, aromatase inhibitory, and microtubule-disrupting agents for breast cancer. Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

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37 pages, 13592 KiB

Open AccessArticle

Design, Synthesis, Anticancer Activity, and Solid Lipid Nanoparticle Formulation of Indole- and Benzimidazole-Based Compounds as Pro-Apoptotic Agents Targeting Bcl-2 Protein

by Manar I. Nagy, Khaled M. Darwish, Safaa M. Kishk, Mohamed A. Tantawy, Ali M. Nasr, Mona Qushawy, Shady A. Swidan, Samia M. Mostafa and Ismail Salama

Pharmaceuticals 2021, 14(2), 113; https://doi.org/10.3390/ph14020113 - 1 Feb 2021

Cited by 18 | Viewed by 4369

Abstract

Cancer is a multifactorial disease necessitating identification of novel targets for its treatment. Inhibition of Bcl-2 for triggered pro-apoptotic signaling is considered a promising strategy for cancer treatment. Within the current work, we aimed to design and synthesize a new series of benzimidazole- [...] Read more.

Cancer is a multifactorial disease necessitating identification of novel targets for its treatment. Inhibition of Bcl-2 for triggered pro-apoptotic signaling is considered a promising strategy for cancer treatment. Within the current work, we aimed to design and synthesize a new series of benzimidazole- and indole-based derivatives as inhibitors of Bcl-2 protein. The market pan-Bcl-2 inhibitor, obatoclax, was the lead framework compound for adopted structural modifications. The obatoclax’s pyrrolylmethine linker was replaced with straight alkylamine or carboxyhydrazine methylene linkers providing the new compounds. This strategy permitted improved structural flexibility of synthesized compounds adopting favored maneuvers for better fitting at the Bcl-2 major hydrophobic pocket. Anti-cancer activity of the synthesized compounds was further investigated through MTT-cytotoxic assay, cell cycle analysis, RT-PCR, ELISA and DNA fragmentation. Cytotoxic results showed compounds 8a, 8b and 8c with promising cytotoxicity against MDA-MB-231/breast cancer cells (IC₅₀ = 12.69 ± 0.84 to 12.83 ± 3.50 µM), while 8a and 8c depicted noticeable activities against A549/lung adenocarcinoma cells (IC₅₀ = 23.05 ± 1.45 and 11.63 ± 2.57 µM, respectively). The signaling Bcl-2 inhibition pathway was confirmed by molecular docking where significant docking energies and interactions with key Bcl-2 pocket residues were depicted. Moreover, the top active compound, 8b, showed significant upregulated expression levels of pro-apoptotic/anti-apoptotic of genes; Bax, Bcl-2, caspase-3, -8, and -9 through RT-PCR assay. Improving the compound’s pharmaceutical profile was undertaken by introducing 8b within drug-solid/lipid nanoparticle formulation prepared by hot melting homogenization technique and evaluated for encapsulation efficiency, particle size, and zeta potential. Significant improvement was seen at the compound’s cytotoxic activity. In conclusion, 8b is introduced as a promising anti-cancer lead candidate that worth future fine-tuned lead optimization and development studies while exploring its potentiality through in-vivo preclinical investigation. Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

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21 pages, 4449 KiB

Open AccessArticle

Discovery of Potent Dual EGFR/HER2 Inhibitors Based on Thiophene Scaffold Targeting H1299 Lung Cancer Cell Line

by Ranza Elrayess, Yasmine M. Abdel Aziz, Mohamed Saleh Elgawish, Marwa Elewa, Asmaa S. A. Yassen, Sameh S. Elhady, Hosam A. Elshihawy and Mohamed M. Said

Pharmaceuticals 2021, 14(1), 9; https://doi.org/10.3390/ph14010009 - 24 Dec 2020

Cited by 21 | Viewed by 3314

Abstract

Dual targeting of epidermal growth factor receptor (EGFR) and human EGFR-related receptor 2 (HER2) is a proven approach for the treatment of lung cancer. With the aim of discovering effective dual EGFR/HER2 inhibitors targeting non-small cell lung cancer cell line H1299, three series [...] Read more.

Dual targeting of epidermal growth factor receptor (EGFR) and human EGFR-related receptor 2 (HER2) is a proven approach for the treatment of lung cancer. With the aim of discovering effective dual EGFR/HER2 inhibitors targeting non-small cell lung cancer cell line H1299, three series of thieno[2,3-d][1,2,3]triazine and acetamide derivatives were designed, synthesized, and biologically evaluated. The synthesized compounds displayed IC₅₀ values ranging from 12 to 54 nM against H1299, which were superior to that of gefitinib (2) at 40 µM. Of the synthesized compounds, 2-(1H-pyrazolo[3,4-b]pyridin-3-ylamino)-N-(3-cyano4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)acetamide (21a) achieved the highest in vitro cytotoxic activity against H1299, with an IC₅₀ value of 12.5 nM in situ, and 0.47 and 0.14 nM against EGFR and HER2, respectively, values comparable to the IC₅₀ of the approved drug imatinib (1). Our synthesized compounds were promising, demonstrating high selectivity and affinity for EGFR/HER2, especially the hinge region forming a hydrophobic pocket, which was mediated by hydrogen bonding as well as hydrophobic and electrostatic interactions, as indicated by molecular modeling. Moreover, the designed compounds showed good affinity for T790M EGFR, one of the main mutants resulting in acquired drug resistance. Furthermore, both pharmacokinetic and physicochemical properties of the designed compounds were within the appropriate range for human usage as predicted by the in Silico ADME study. The designed compound (21a) might serve as an encouraging lead compound for the discovery of promising anti-lung cancer agents targeting EGFR/HER2. Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

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24 pages, 3232 KiB

Open AccessArticle

Exploring the Anti-Cancer Mechanism of Novel 3,4′-Substituted Diaryl Guanidinium Derivatives

by Viola Previtali, Helene B. Mihigo, Rebecca Amet, Anthony M. McElligott, Daniela M. Zisterer and Isabel Rozas

Pharmaceuticals 2020, 13(12), 485; https://doi.org/10.3390/ph13120485 - 21 Dec 2020

Cited by 4 | Viewed by 3058

Abstract

We previously identified a guanidinium-based lead compound that inhibited BRAF through a hypothetic type-III allosteric mechanism. Considering the pharmacophore identified in this lead compound (i.e., “lipophilic group”, “di-substituted guanidine”, “phenylguanidine polar end”), several modifications were investigated to improve its cytotoxicity in different cancer [...] Read more.

We previously identified a guanidinium-based lead compound that inhibited BRAF through a hypothetic type-III allosteric mechanism. Considering the pharmacophore identified in this lead compound (i.e., “lipophilic group”, “di-substituted guanidine”, “phenylguanidine polar end”), several modifications were investigated to improve its cytotoxicity in different cancer cell lines. Thus, several lipophilic groups were explored, the di-substituted guanidine was replaced by a secondary amine and the phenyl ring in the polar end was substituted by a pyridine. In a structure-based design approach, four representative derivatives were docked into an in-house model of an active triphosphate-containing BRAF protein, and the interactions established were analysed. Based on these computational studies, a variety of derivatives was synthesized, and their predicted drug-like properties calculated. Next, the effect on cell viability of these compounds was assessed in cell line models of promyelocytic leukaemia and breast, cervical and colorectal carcinomas. The potential of a selection of these compounds as apoptotic agents was assessed by screening in the promyelocytic leukaemia cell line HL-60. The toxicity against non-tumorigenic epithelial MCF10A cells was also investigated. These studies allowed for several structure-activity relationships to be derived. Investigations on the mechanism of action of representative compounds suggest a divergent effect on inhibition of the MAPK/ERK signalling pathway. Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

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15 pages, 2828 KiB

Open AccessArticle

Synthesis of New 1, 3, 4-Oxadiazole-Incorporated 1, 2, 3-Triazole Moieties as Potential Anticancer Agents Targeting Thymidylate Synthase and Their Docking Studies

by Mohammad Mahboob Alam, Abdulraheem SA Almalki, Thikryat Neamatallah, Nada M. Ali, Azizah M. Malebari and Syed Nazreen

Pharmaceuticals 2020, 13(11), 390; https://doi.org/10.3390/ph13110390 - 14 Nov 2020

Cited by 45 | Viewed by 4156

Abstract

Thymidylate synthase (TS) has emerged as a hot spot in cancer treatment, as it is directly involved in DNA synthesis. In the present article, nine hybrids containing 1,2,3-triazole and 1,3,4-oxadiazole moieties (6–14) were synthesized and evaluated for anticancer and [...] Read more.

Thymidylate synthase (TS) has emerged as a hot spot in cancer treatment, as it is directly involved in DNA synthesis. In the present article, nine hybrids containing 1,2,3-triazole and 1,3,4-oxadiazole moieties (6–14) were synthesized and evaluated for anticancer and in vitro thymidylate synthase activities. According to in silico pharmacokinetic studies, the synthesized hybrids exhibited good drug likeness properties and bioavailability. The cytotoxicity results indicated that compounds 12 and 13 exhibited remarkable inhibition on the tested Michigan Cancer Foundation (MCF-7) and Human colorectal Carcinoma (HCT-116) cell lines. Compound 12 showed four-fold inhibition to a standard drug, 5-fluoruracil, and comparable inhibition to tamoxifen, whereas compound 13 exerted five-fold activity of tamoxifen and 24-fold activity of 5-fluorouracil for MCF-7 cells. Compounds 12 and 13 inhibited thymidylate synthase enzyme, with an half maximal inhibitory concentration, IC₅₀ of 2.52 µM and 4.38 µM, while a standard drug, pemetrexed, showed IC₅₀ = 6.75 µM. The molecular docking data of compounds 12 and 13 were found to be in support of biological activities data. In conclusion, hybrids (12 and 13) may inhibit thymidylate synthase enzyme, which could play a significant role as a chemotherapeutic agent. Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

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Review

Jump to: Editorial, Research

39 pages, 2966 KiB

Open AccessEditor’s ChoiceReview

An Update on the Anticancer Activity of Xanthone Derivatives: A Review

by Yehezkiel Steven Kurniawan, Krisfian Tata Aneka Priyangga, Jumina, Harno Dwi Pranowo, Eti Nurwening Sholikhah, Abdul Karim Zulkarnain, Hana Anisa Fatimi and Jeffry Julianus

Pharmaceuticals 2021, 14(11), 1144; https://doi.org/10.3390/ph14111144 - 11 Nov 2021

Cited by 53 | Viewed by 6377

Abstract

The annual number of cancer deaths continues increasing every day; thus, it is urgent to search for and find active, selective, and efficient anticancer drugs as soon as possible. Among the available anticancer drugs, almost all of them contain heterocyclic moiety in their [...] Read more.

The annual number of cancer deaths continues increasing every day; thus, it is urgent to search for and find active, selective, and efficient anticancer drugs as soon as possible. Among the available anticancer drugs, almost all of them contain heterocyclic moiety in their chemical structure. Xanthone is a heterocyclic compound with a dibenzo-γ-pyrone framework and well-known to have “privileged structures” for anticancer activities against several cancer cell lines. The wide anticancer activity of xanthones is produced by caspase activation, RNA binding, DNA cross-linking, as well as P-gp, kinase, aromatase, and topoisomerase inhibition. This anticancer activity depends on the type, number, and position of the attached functional groups in the xanthone skeleton. This review discusses the recent advances in the anticancer activity of xanthone derivatives, both from natural products isolation and synthesis methods, as the anticancer agent through in vitro, in vivo, and clinical assays. Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

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26 pages, 1884 KiB

Open AccessReview

Mucin1 and Mucin16: Therapeutic Targets for Cancer Therapy

by Dong-Hee Lee, Seunghyun Choi, Yoon Park and Hyung-seung Jin

Pharmaceuticals 2021, 14(10), 1053; https://doi.org/10.3390/ph14101053 - 17 Oct 2021

Cited by 44 | Viewed by 9290

Abstract

The mucin (MUC) family is a group of highly glycosylated macromolecules that are abundantly expressed in mammalian epithelial cells. MUC proteins contribute to the formation of the mucus barrier and thus have protective functions against infection. Interestingly, some MUC proteins are aberrantly expressed [...] Read more.

The mucin (MUC) family is a group of highly glycosylated macromolecules that are abundantly expressed in mammalian epithelial cells. MUC proteins contribute to the formation of the mucus barrier and thus have protective functions against infection. Interestingly, some MUC proteins are aberrantly expressed in cancer cells and are involved in cancer development and progression, including cell growth, proliferation, the inhibition of apoptosis, chemoresistance, metabolic reprogramming, and immune evasion. With their unique biological and structural features, MUC proteins have been considered promising therapeutic targets and also biomarkers for human cancer. In this review, we discuss the biological roles of the transmembrane mucins MUC1 and MUC16 in the context of hallmarks of cancer and current efforts to develop MUC1- and MUC16-targeted therapies. Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

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59 pages, 10396 KiB

Open AccessReview

Innovations and Patent Trends in the Development of USFDA Approved Protein Kinase Inhibitors in the Last Two Decades

by Mohd. Imran, Syed Mohammed Basheeruddin Asdaq, Shah Alam Khan, Dhanalekshmi Unnikrishnan Meenakshi, Abdulhakeem S. Alamri, Walaa F. Alsanie, Majid Alhomrani, Yahya Mohzari, Ahmed Alrashed, Mohammed AlMotairi, Eman H. Alkhaldi, Abeer K. Alorabi, Ahmed Subeh Alshrari, Mohammad Tauseef, Abida, Saleh I. Alaqel, Ozair Alam and Md. Afroz Bakht

Pharmaceuticals 2021, 14(8), 710; https://doi.org/10.3390/ph14080710 - 22 Jul 2021

Cited by 29 | Viewed by 7371

Abstract

Protein kinase inhibitors (PKIs) are important therapeutic agents. As of 31 May 2021, the United States Food and Drug Administration (USFDA) has approved 70 PKIs. Most of the PKIs are employed to treat cancer and inflammatory diseases. Imatinib was the first PKI approved [...] Read more.

Protein kinase inhibitors (PKIs) are important therapeutic agents. As of 31 May 2021, the United States Food and Drug Administration (USFDA) has approved 70 PKIs. Most of the PKIs are employed to treat cancer and inflammatory diseases. Imatinib was the first PKI approved by USFDA in 2001. This review summarizes the compound patents and the essential polymorph patents of the PKIs approved by the USFDA from 2001 to 31 May 2021. The dates on the generic drug availability of the PKIs in the USA market have also been forecasted. It is expected that 19 and 48 PKIs will be genericized by 2025 and 2030, respectively, due to their compound patent expiry. This may reduce the financial toxicity associated with the existing PKIs. There are nearly 535 reported PKs. However, the USFDA approved PKIs target only about 10–15% of the total said PKs. As a result, there are still a large number of unexplored PKs. As the field advances during the next 20 years, one can anticipate that PKIs with many scaffolds, chemotypes, and pharmacophores will be developed. Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

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11 pages, 1008 KiB

Open AccessReview

TRK Inhibitors: Tissue-Agnostic Anti-Cancer Drugs

by Sun-Young Han

Pharmaceuticals 2021, 14(7), 632; https://doi.org/10.3390/ph14070632 - 29 Jun 2021

Cited by 17 | Viewed by 4453

Abstract

Recently, two tropomycin receptor kinase (Trk) inhibitors, larotrectinib and entrectinib, have been approved for Trk fusion-positive cancer patients. Clinical trials for larotrectinib and entrectinib were performed with patients selected based on the presence of Trk fusion, regardless of cancer type. This unique approach, [...] Read more.

Recently, two tropomycin receptor kinase (Trk) inhibitors, larotrectinib and entrectinib, have been approved for Trk fusion-positive cancer patients. Clinical trials for larotrectinib and entrectinib were performed with patients selected based on the presence of Trk fusion, regardless of cancer type. This unique approach, called tissue-agnostic development, expedited the process of Trk inhibitor development. In the present review, the development processes of larotrectinib and entrectinib have been described, along with discussion on other Trk inhibitors currently in clinical trials. The on-target effects of Trk inhibitors in Trk signaling exhibit adverse effects on the central nervous system, such as withdrawal pain, weight gain, and dizziness. A next generation sequencing-based method has been approved for companion diagnostics of larotrectinib, which can detect various types of Trk fusions in tumor samples. With the adoption of the tissue-agnostic approach, the development of Trk inhibitors has been accelerated. Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

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