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15 pages, 4692 KiB

Open AccessArticle

Design, Synthesis, and Cytotoxic Assessment of New Haloperidol Analogues as Potential Anticancer Compounds Targeting Sigma Receptors

by Daniele Zampieri, Maurizio Romano, Sara Fortuna, Emanuele Amata, Maria Dichiara, Giuseppe Cosentino, Agostino Marrazzo and Maria Grazia Mamolo

Molecules 2024, 29(11), 2697; https://doi.org/10.3390/molecules29112697 - 6 Jun 2024

Viewed by 1019

Abstract

Sigma receptors (SRs), including SR1 and SR2 subtypes, have attracted increasing interest in recent years due to their involvement in a wide range of activities, including the modulation of opioid analgesia, neuroprotection, and potential anticancer activity. In this context, haloperidol (HAL), a commonly [...] Read more.

Sigma receptors (SRs), including SR1 and SR2 subtypes, have attracted increasing interest in recent years due to their involvement in a wide range of activities, including the modulation of opioid analgesia, neuroprotection, and potential anticancer activity. In this context, haloperidol (HAL), a commonly used antipsychotic drug, also possesses SR activity and cytotoxic effects. Herein, we describe the identification of novel SR ligands, obtained by a chemical hybridization approach. There wereendowed with pan-affinity for both SR subtypes and evaluated their potential anticancer activity against SH-SY5Y and HUH-7 cancer cell lines. Through a chemical hybridization approach, we identified novel compounds (4d, 4e, 4g, and 4j) with dual affinity for SR1 and SR2 receptors. These compounds were subjected to cytotoxicity testing using a resazurin assay. The results revealed potent cytotoxic effects against both cancer cell lines, with IC₅₀ values comparable to HAL. Interestingly, the cytotoxic potency of the novel compounds resembled that of the SR1 antagonist HAL rather than the SR2 agonist siramesine (SRM), indicating the potential role of SR1 antagonism in their mechanism of action. The further exploration of their structure-activity relationships and their evaluation in additional cancer cell lines will elucidate their therapeutic potential and may pave the way for the development of novel anticancer agents that target SRs. Full article

(This article belongs to the Special Issue Small Molecules in Targeted Cancer Therapy)

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18 pages, 5699 KiB

Open AccessArticle

Identifying the Multitarget Pharmacological Mechanism of Action of Genistein on Lung Cancer by Integrating Network Pharmacology and Molecular Dynamic Simulation

by Raju Das and Joohan Woo

Molecules 2024, 29(9), 1913; https://doi.org/10.3390/molecules29091913 - 23 Apr 2024

Viewed by 1756

Abstract

Food supplements have become beneficial as adjuvant therapies for many chronic disorders, including cancer. Genistein, a natural isoflavone enriched in soybeans, has gained potential interest as an anticancer agent for various cancers, primarily by modulating apoptosis, the cell cycle, and angiogenesis and inhibiting [...] Read more.

Food supplements have become beneficial as adjuvant therapies for many chronic disorders, including cancer. Genistein, a natural isoflavone enriched in soybeans, has gained potential interest as an anticancer agent for various cancers, primarily by modulating apoptosis, the cell cycle, and angiogenesis and inhibiting metastasis. However, in lung cancer, the exact impact and mechanism of action of genistein still require clarification. To provide more insight into the mechanism of action of genistein, network pharmacology was employed to identify the key targets and their roles in lung cancer pathogenesis. Based on the degree score, the hub genes AKT1, CASP3, EGFR, STAT3, ESR1, SRC, PTGS2, MMP9, PRAG, and AR were significantly correlated with genistein treatment. AKT1, EGFR, and STAT3 were enriched in the non-small cell lung cancer (NSCLC) pathway according to Kyoto Encyclopedia of Genes and Genomes analysis, indicating a significant connection to lung cancer development. Moreover, the binding affinity of genistein to NSCLC target proteins was further verified by molecular docking and molecular dynamics simulations. Genistein exhibited potential binding to AKT1, which is involved in apoptosis, cell migration, and metastasis, thus holding promise for modulating AKT1 function. Therefore, this study aimed to investigate the mechanism of action of genistein and its therapeutic potential for the treatment of NSCLC. Full article

(This article belongs to the Special Issue Small Molecules in Targeted Cancer Therapy)

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20 pages, 3832 KiB

Open AccessArticle

Design, Synthesis, Computational Studies, and Anti-Proliferative Evaluation of Novel Ethacrynic Acid Derivatives Containing Nitrogen Heterocycle, Urea, and Thiourea Moieties as Anticancer Agents

by Abdelmoula El Abbouchi, Khaoula Mkhayar, Souad Elkhattabi, Nabil El Brahmi, Marie-Aude Hiebel, Jérôme Bignon, Gérald Guillaumet, Franck Suzenet and Saïd El Kazzouli

Molecules 2024, 29(7), 1437; https://doi.org/10.3390/molecules29071437 - 23 Mar 2024

Cited by 1 | Viewed by 1417

Abstract

In the present work, the synthesis of new ethacrynic acid (EA) derivatives containing nitrogen heterocyclic, urea, or thiourea moieties via efficient and practical synthetic procedures was reported. The synthesised compounds were screened for their anti-proliferative activity against two different cancer cell [...] Read more.

In the present work, the synthesis of new ethacrynic acid (EA) derivatives containing nitrogen heterocyclic, urea, or thiourea moieties via efficient and practical synthetic procedures was reported. The synthesised compounds were screened for their anti-proliferative activity against two different cancer cell lines, namely, HL60 (promyelocytic leukaemia) and HCT116 (human colon carcinoma). The results of the in vitro tests reveal that compounds 1–3, 10, 16(a–c), and 17 exhibit potent anti-proliferative activity against the HL60 cell line, with values of the percentage of cell viability ranging from 20 to 35% at 1 μM of the drug and IC₅₀ values between 2.37 μM and 0.86 μM. Compounds 2 and 10 showed a very interesting anti-proliferative activity of 28 and 48% at 1 μM, respectively, against HCT116. Two PyTAP-based fluorescent EA analogues were also synthesised and tested, showing good anti-proliferative activity. A test on the drug-likeness properties in silico of all the synthetised compounds was performed in order to understand the mechanism of action of the most active compounds. A molecular docking study was conducted on two human proteins, namely, glutathione S-transferase P1-1 (pdb:2GSS) and caspase-3 (pdb:4AU8) as target enzymes. The docking results show that compounds 2 and 3 exhibit significant binding modes with these enzymes. This finding provides a potential strategy towards developing anticancer agents, and most of the synthesised and newly designed compounds show good drug-like properties. Full article

(This article belongs to the Special Issue Small Molecules in Targeted Cancer Therapy)

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24 pages, 4901 KiB

Open AccessArticle

Exploring Thiazolopyridine AV25R: Unraveling of Biological Activities, Selective Anti-Cancer Properties and In Silico Target and Binding Prediction in Hematological Neoplasms

by Annika Ladwig, Shailendra Gupta, Peter Ehlers, Anett Sekora, Moosheer Alammar, Dirk Koczan, Olaf Wolkenhauer, Christian Junghanss, Peter Langer and Hugo Murua Escobar

Molecules 2023, 28(24), 8120; https://doi.org/10.3390/molecules28248120 - 15 Dec 2023

Viewed by 1280

Abstract

Thiazolopyridines are a highly relevant class of small molecules, which have previously shown a wide range of biological activities. Besides their anti-tubercular, anti-microbial and anti-viral activities, they also show anti-cancerogenic properties, and play a role as inhibitors of cancer-related proteins. Herein, the biological [...] Read more.

Thiazolopyridines are a highly relevant class of small molecules, which have previously shown a wide range of biological activities. Besides their anti-tubercular, anti-microbial and anti-viral activities, they also show anti-cancerogenic properties, and play a role as inhibitors of cancer-related proteins. Herein, the biological effects of the thiazolopyridine AV25R, a novel small molecule with unknown biological effects, were characterized. Screening of a set of lymphoma (SUP-T1, SU-DHL-4) and B- acute leukemia cell lines (RS4;11, SEM) revealed highly selective effects of AV25R. The selective anti-proliferative and metabolism-modulating effects were observed in vitro for the B-ALL cell line RS4;11. Further, we were able to detect severe morphological changes and the induction of apoptosis. Gene expression analysis identified a large number of differentially expressed genes after AV25R exposure and significant differentially regulated cancer-related signaling pathways, such as VEGFA-VEGFR2 signaling and the EGF/EGFR pathway. Structure-based pharmacophore screening approaches using in silico modeling identified potential biological AV25R targets. Our results indicate that AV25R binds with several proteins known to regulate cell proliferation and tumor progression, such as FECH, MAP11, EGFR, TGFBR1 and MDM2. The molecular docking analyses indicates that AV25R has a higher binding affinity compared to many of the experimentally validated small molecule inhibitors of these targets. Thus, here we present in vitro and in silico analyses which characterize, for the first time, the molecular acting mechanism of AV25R, including cellular and molecular biologic effects. Additionally, this predicted the target binding of the molecule, revealing a high affinity to cancer-related proteins and, thus, classified AVR25 for targeted intervention approaches. Full article

(This article belongs to the Special Issue Small Molecules in Targeted Cancer Therapy)

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14 pages, 1600 KiB

Open AccessArticle

Retention Behavior of Anticancer Thiosemicarbazides in Biomimetic Chromatographic Systems and In Silico Calculations

by Marek Studziński, Paweł Kozyra, Monika Pitucha, Bogusław Senczyna and Joanna Matysiak

Molecules 2023, 28(20), 7107; https://doi.org/10.3390/molecules28207107 - 16 Oct 2023

Viewed by 1103

Abstract

Chromatographic methods, apart from in silico ones, are commonly used rapid techniques for the evaluation of certain properties of biologically active compounds used for their prediction of pharmacokinetic processes. Thiosemicarbazides are compounds possessing anticancer, antimicrobial, and other valuable biological activities. The aim of [...] Read more.

Chromatographic methods, apart from in silico ones, are commonly used rapid techniques for the evaluation of certain properties of biologically active compounds used for their prediction of pharmacokinetic processes. Thiosemicarbazides are compounds possessing anticancer, antimicrobial, and other valuable biological activities. The aim of the investigation was to estimate the lipophilicity of 1-aryl-4-(phenoxy)acetylthiosemicarbazides, to predict their oral adsorption and the assessment of their % plasma–protein binding (%PPB). RP-HPLC chromatographic techniques with five diversified HPLC systems, including columns with surface-bonded octadecylsilanes (C-18), phosphatidylcholine (immobilized artificial membrane, IAM), cholesterol (Chol), and α1-acid glycoprotein (AGP) and human serum albumin (HSA), were applied. The measured lipophilicity of all investigated compounds was within the range recommended for potential drug candidates. However, some derivatives are strongly bonded to HSA (%PPB ≈ 100%), which may limit some pharmacokinetic processes. HPLC determined lipophilicity descriptors were compared with those obtained by various computational approaches. Full article

(This article belongs to the Special Issue Small Molecules in Targeted Cancer Therapy)

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20 pages, 6790 KiB

Open AccessArticle

Discovery of a SHP2 Degrader with In Vivo Anti-Tumor Activity

by Jinmin Miao, Yunpeng Bai, Yiming Miao, Zihan Qu, Jiajun Dong, Ruo-Yu Zhang, Devesh Aggarwal, Brenson A. Jassim, Quyen Nguyen and Zhong-Yin Zhang

Molecules 2023, 28(19), 6947; https://doi.org/10.3390/molecules28196947 - 6 Oct 2023

Cited by 4 | Viewed by 2911

Abstract

Src homology 2 domain-containing phosphatase 2 (SHP2) is an attractive target for cancer therapy due to its multifaceted roles in both tumor and immune cells. Herein, we designed and synthesized a novel series of proteolysis targeting chimeras (PROTACs) using a SHP2 allosteric inhibitor [...] Read more.

Src homology 2 domain-containing phosphatase 2 (SHP2) is an attractive target for cancer therapy due to its multifaceted roles in both tumor and immune cells. Herein, we designed and synthesized a novel series of proteolysis targeting chimeras (PROTACs) using a SHP2 allosteric inhibitor as warhead, with the goal of achieving SHP2 degradation both inside the cell and in vivo. Among these molecules, compound P9 induces efficient degradation of SHP2 (DC₅₀ = 35.2 ± 1.5 nM) in a concentration- and time-dependent manner. Mechanistic investigation illustrates that the P9-mediated SHP2 degradation requires the recruitment of the E3 ligase and is ubiquitination- and proteasome-dependent. P9 shows improved anti-tumor activity in a number of cancer cell lines over its parent allosteric inhibitor. Importantly, administration of P9 leads to a nearly complete tumor regression in a xenograft mouse model, as a result of robust SHP2 depletion and suppression of phospho-ERK1/2 in the tumor. Hence, P9 represents the first SHP2 PROTAC molecule with excellent in vivo efficacy. It is anticipated that P9 could serve not only as a new chemical tool to interrogate SHP2 biology but also as a starting point for the development of novel therapeutics targeting SHP2. Full article

(This article belongs to the Special Issue Small Molecules in Targeted Cancer Therapy)

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13 pages, 2217 KiB

Open AccessArticle

Anlotinib Exerts Inhibitory Effects against Cisplatin-Resistant Ovarian Cancer In Vitro and In Vivo

by Yurou Ji, Xinyu Li, Yue Qi, Jianguo Zhao, Wenwen Zhang and Pengpeng Qu

Molecules 2022, 27(24), 8873; https://doi.org/10.3390/molecules27248873 - 14 Dec 2022

Cited by 2 | Viewed by 2297

Abstract

Background: Anlotinib is a highly potent multi-target tyrosine kinase inhibitor. Accumulating evidence suggests that anlotinib exhibits effective anti-tumor activity against various cancer subtypes. However, the effects of anlotinib against cisplatin-resistant (CIS) ovarian cancer (OC) are yet to be elucidated. The objective of this [...] Read more.

Background: Anlotinib is a highly potent multi-target tyrosine kinase inhibitor. Accumulating evidence suggests that anlotinib exhibits effective anti-tumor activity against various cancer subtypes. However, the effects of anlotinib against cisplatin-resistant (CIS) ovarian cancer (OC) are yet to be elucidated. The objective of this study was to investigate the inhibitory effect of anlotinib on the pathogenesis of cisplatin-resistant OC. Materials and Methods: Human OC cell lines (A2780 and A2780 CIS) were cultured and treated with or without anlotinib. The effects of anlotinib on cell proliferation were determined using cell-counting kit-8 and colony-formation assays. To evaluate the invasion and metastasis of OC cells, we performed wound-healing and transwell assays. The cell cycle was analyzed via flow cytometry. A xenograft mouse model was used to conduct in vivo studies to verify the effects of anlotinib. The expression of Ki-67 in the tumor tissue was detected via immunohistochemistry. Quantitative real-time polymerase chain reaction and Western blotting were used to measure the mRNA and protein levels. Results: Our study revealed that anlotinib significantly inhibited the proliferation, migration, and invasion of A2780 and A2780 CIS in a dose-dependent way in vitro (p < 0.05). Through R software ‘limma’ package analysis of GSE15372, it was found that, in comparison with A2780, PLK2 was expressed in significantly low levels in the corresponding cisplatin-resistant strains. The ERK1/2/Plk2 signaling axis mediates the inhibitory effect of anlotinib on the proliferation and migration of ovarian cancer cell lines. Moreover, our research found that anlotinib effectively inhibited the growth of tumor cells in an OC xenograft mouse model. Conclusions: In this study, anlotinib showed excellent inhibitory effects against cisplatin-resistant OC both in vitro and in vivo. These results add to the growing body of evidence supporting anlotinib as a potential anticancer agent against OC. Full article

(This article belongs to the Special Issue Small Molecules in Targeted Cancer Therapy)

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16 pages, 2747 KiB

Open AccessArticle

Dual Targeting of MDM4 and FTH1 by MMRi71 for Induced Protein Degradation and p53-Independent Apoptosis in Leukemia Cells

by Rati Lama, Samuel L. Galster, Chao Xu, Luke W. Davison, Sherry R. Chemler and Xinjiang Wang

Molecules 2022, 27(22), 7665; https://doi.org/10.3390/molecules27227665 - 8 Nov 2022

Cited by 1 | Viewed by 2090

Abstract

MDM2 and MDM4 are cancer drug targets validated in multiple models for p53-based cancer therapies. The RING domains of MDM2 and non-p53-binder MDM2 splice isoforms form RING domain heterodimer polyubiquitin E3 ligases with MDM4, which regulate p53 stability in vivo and promote tumorigenesis [...] Read more.

MDM2 and MDM4 are cancer drug targets validated in multiple models for p53-based cancer therapies. The RING domains of MDM2 and non-p53-binder MDM2 splice isoforms form RING domain heterodimer polyubiquitin E3 ligases with MDM4, which regulate p53 stability in vivo and promote tumorigenesis independent of p53. Despite the importance of the MDM2 RING domain in p53 regulation and cancer development, small molecule inhibitors targeting the E3 ligase activity of MDM2-MDM4 are poorly explored. Here, we describe the synthesis and characterization of quinolinol derivatives for the identification of analogs that are capable of targeting the MDM2-MDM4 heterodimer E3 ligase and inducing apoptosis in cells. The structure-activity-relationship (SAR) study identified structural moieties critical for the inhibitory effects toward MDM2-MDM4 E3 ligase, the targeted degradation of MDM4 and FTH1 in cells, and anti-proliferation activity. Lead optimization led to the development of compound MMRi71 with improved activity. In addition to accumulating p53 proteins in wt-p53 bearing cancer cells as expected of any MDM2 inhibitors, MMRi71 effectively kills p53-null leukemia cells, an activity that conventional MDM2-p53 disrupting inhibitors lack. This study provides a prototype structure for developing MDM4/FTH1 dual-targeting inhibitors as potential cancer therapeutics. Full article

(This article belongs to the Special Issue Small Molecules in Targeted Cancer Therapy)

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19 pages, 5455 KiB

Open AccessArticle

AVA-NP-695 Selectively Inhibits ENPP1 to Activate STING Pathway and Abrogate Tumor Metastasis in 4T1 Breast Cancer Syngeneic Mouse Model

by Avijit Goswami, Barnali Deb, Sandeep Goyal, Abhishek Gosavi, Mukund Mali, Ashwita M. Martis, Princy Khurana, Mukesh Gangar, Digambar Raykar, Ankita Mohanty and Aditya Kulkarni

Molecules 2022, 27(19), 6721; https://doi.org/10.3390/molecules27196721 - 9 Oct 2022

Cited by 12 | Viewed by 5228

Abstract

Cyclic GMP-AMP synthase (cGAS) is an endogenous DNA sensor that synthesizes cyclic guanosine monophosphate–adenosine monophosphate (2′3′-cGAMP) from ATP and GTP. 2′3′-cGAMP activates the stimulator of interferon genes (STING) pathway, resulting in the production of interferons and pro-inflammatory cytokines. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is [...] Read more.

Cyclic GMP-AMP synthase (cGAS) is an endogenous DNA sensor that synthesizes cyclic guanosine monophosphate–adenosine monophosphate (2′3′-cGAMP) from ATP and GTP. 2′3′-cGAMP activates the stimulator of interferon genes (STING) pathway, resulting in the production of interferons and pro-inflammatory cytokines. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is the phosphodiesterase that negatively regulates the STING pathway by hydrolyzing 2′3′-cGAMP. It has been established that the cGAS–STING pathway plays a major role in inhibiting tumor growth by upregulating T cell response. Herein, we demonstrate that AVA-NP-695, a selective and highly potent ENPP1 inhibitor, apart from the immunomodulatory effect also modulates cancer metastasis by negatively regulating epithelial–mesenchymal transition (EMT). We established that the combined addition of 2′3′-cGAMP and AVA-NP-695 significantly abrogated the transforming growth factor beta (TGF-ꞵ)-induced EMT in MDA-MB-231 cells. Finally, results from the in vivo study showed superior tumor growth inhibition and impact on tumor metastasis of AVA-NP-695 compared to Olaparib and PD-1 in a syngeneic 4T1 breast cancer mouse model. The translation of efficacy from in vitro to in vivo 4T1 tumor model provides a strong rationale for the therapeutic potential of AVA-NP-695 against triple-negative breast cancer (TNBC) as an immunomodulatory and anti-metastatic agent. Full article

(This article belongs to the Special Issue Small Molecules in Targeted Cancer Therapy)

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Review

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16 pages, 741 KiB

Open AccessReview

Precious Gene: The Application of RET-Altered Inhibitors

by Qitao Gou, Xiaochuan Gan, Longhao Li, Qiheng Gou and Tao Zhang

Molecules 2022, 27(24), 8839; https://doi.org/10.3390/molecules27248839 - 13 Dec 2022

Cited by 1 | Viewed by 3136

Abstract

The well-known proto-oncogene rearrangement during transfection (RET), also known as ret proto-oncogene Homo sapiens (human), is a rare gene that is involved in the physiological development of some organ systems and can activate various cancers, such as non-small cell lung cancer, thyroid cancer, [...] Read more.

The well-known proto-oncogene rearrangement during transfection (RET), also known as ret proto-oncogene Homo sapiens (human), is a rare gene that is involved in the physiological development of some organ systems and can activate various cancers, such as non-small cell lung cancer, thyroid cancer, and papillary thyroid cancer. In the past few years, cancers with RET alterations have been treated with multikinase inhibitors (MKIs). However, because of off-target effects, these MKIs have developed drug resistance and some unacceptable adverse effects. Therefore, these MKIs are limited in their clinical application. Thus, the novel highly potent and RET-specific inhibitors selpercatinib and pralsetinib have been accelerated for approval by the Food and Drug Administration (FDA), and clinical trials of TPX-0046 and zetletinib are underway. It is well tolerated and a potential therapeutic for RET-altered cancers. Thus, we will focus on current state-of-the-art therapeutics with these novel RET inhibitors and show their efficacy and safety in therapy. Full article

(This article belongs to the Special Issue Small Molecules in Targeted Cancer Therapy)

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