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Kinase Inhibitors II

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (28 February 2019) | Viewed by 34679

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Prof. Dr. Christian Peifer

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Department of Pharmaceutical Chemistry, Christian Albrechts University, Gutenbergstraße 76, 24118 Kiel, Germany
Interests: design; synthesis and biological evaluation of protein kinase inhibitors
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Dear Colleagues,

Since the discovery of protein phosphorylation as a post-translational modification in glycogen metabolism in the1960s, protein kinases (PK) and their opponents, phosphatases, have been crucial to many scientists. Approximately 2% of the human genome encodes for PKs, named the human “kinome”, consisting of 518 PKs and their splice variants. PKs typically use ATP for γ-phosphor-transfer reactions for OH-functions of serine, threonine, or tyrosine residues in proteins. In fact, the relatively simple attachment of a phosphate moiety induces critical conformational and functional changes of the substrate protein. Due to the powerful nature of protein modification involved in key cellular processes, such as signal transduction, cell cycle, metabolism, differentiation, and cell survival, PKs have to be strictly regulated in a physiological context. In contrast, their dysregulation leads to severe diseases, including cancer. In line with this notion, the first proto-oncogene c-SRC was identified as a non-receptor tyrosine kinase in 1978.

Today, PKs are validated and widely accepted targets for drug discovery, triggered significantly by the clinical success of imatinib in 2001. Thus far, more than 40 drugs have been FDA-approved and are on the market. The majority of compounds address tyrosine kinases, with their main therapeutical applications being cancer and inflammation. In addition to massive commercial drug discovery programs for the development of kinase inhibitors, academia has contributed a solid part to today´s knowledge on PK and their inhibitors. A wealth of biological studies towards the validation of PKs as drug targets, hit-compounds, lead structures, pharmacological tools, and ligand–protein complexes for the development of novel PK inhibitors are reported in literature. The topics cover various scientific areas, including molecular biology, biological and medicinal chemistry, and clinical applications.

This Special Issue of Molecules will focus on the exciting area of protein kinases and novel approaches in PK drug discovery.

Prof. Dr. Christian Peifer
Guest Editor

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Keywords

protein phosphorylation
signal transduction
small molecule kinase inhibitors (smKI)
receptor tyrosine kinases
serin-threonine kinases
pseudokinases
Type I-VI
DFGin
DFGout
hinge-binder
gatekeeper-residue
ATP competitive/alosteric/covalent inhibition
kinome-screening selectivity
518 human protein kinases
in-vitro activity/in-vivo efficacy
mutated kinases,
rational structure- based design
medicinal chemistry/drug discovery
targeted therapy
personalized medicine

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Published Papers (7 papers)

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Research

17 pages, 3861 KiB

Open AccessArticle

Comparative Assessment of Protein Kinase Inhibitors in Public Databases and in PKIDB

by Colin Bournez, Fabrice Carles, Gautier Peyrat, Samia Aci-Sèche, Stéphane Bourg, Christophe Meyer and Pascal Bonnet

Molecules 2020, 25(14), 3226; https://doi.org/10.3390/molecules25143226 - 15 Jul 2020

Cited by 48 | Viewed by 5884

Abstract

Since the first approval of a protein kinase inhibitor (PKI) by the Food and Drug Administration (FDA) in 2001, 55 new PKIs have reached the market, and many inhibitors are currently being evaluated in clinical trials. This is a clear indication that protein kinases still represent major drug targets for the pharmaceutical industry. In a previous work, we have introduced PKIDB, a publicly available database, gathering PKIs that have already been approved (Phase 4), as well as those currently in clinical trials (Phases 0 to 3). This database is updated frequently, and an analysis of the new data is presented here. In addition, we compared the set of PKIs present in PKIDB with the PKIs in early preclinical studies found in ChEMBL, the largest publicly available chemical database. For each dataset, the distribution of physicochemical descriptors related to drug-likeness is presented. From these results, updated guidelines to prioritize compounds for targeting protein kinases are proposed. The results of a principal component analysis (PCA) show that the PKIDB dataset is fully encompassed within all PKIs found in the public database. This observation is reinforced by a principal moments of inertia (PMI) analysis of all molecules. Interestingly, we notice that PKIs in clinical trials tend to explore new 3D chemical space. While a great majority of PKIs is located on the area of “flatland”, we find few compounds exploring the 3D structural space. Finally, a scaffold diversity analysis of the two datasets, based on frequency counts was performed. The results give insight into the chemical space of PKIs, and can guide researchers to reach out new unexplored areas. PKIDB is freely accessible from the following website: http://www.icoa.fr/pkidb. Full article

(This article belongs to the Special Issue Kinase Inhibitors II)

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13 pages, 3320 KiB

Open AccessCommunication

New Insights into 4-Anilinoquinazolines as Inhibitors of Cardiac Troponin I–Interacting Kinase (TNNi3K)

by Christopher R. M. Asquith, Tuomo Laitinen, Carrow I. Wells, Graham J. Tizzard and William J. Zuercher

Molecules 2020, 25(7), 1697; https://doi.org/10.3390/molecules25071697 - 7 Apr 2020

Cited by 8 | Viewed by 2970

Abstract

We report the synthesis of several related 4-anilinoquinazolines as inhibitors of cardiac troponin I–interacting kinase (TNNi3K). These close structural analogs of 3-((6,7-dimethoxyquinazolin-4-yl)amino)-4-(dimethylamino)-N-methylbenzenesulfonamide (GSK114) provide new understanding of structure–activity relationships between the 4-anilinoquinazoline scaffold and TNNi3K inhibition. Through a small focused library of inhibitors, we observed that the N-methylbenzenesulfonamide was driving the potency in addition to the more traditional quinazoline hinge-binding motif. We also identified a compound devoid of TNNi3K kinase activity due to the addition of a methyl group in the hinge binding region. This compound could serve as a negative control in the study of TNNi3K biology. Small molecule crystal structures of several quinazolines have been solved, supporting observations made about overall conformation and TNNi3K inhibition. Full article

(This article belongs to the Special Issue Kinase Inhibitors II)

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31 pages, 6392 KiB

Open AccessArticle

Design, Synthesis and Biological Evaluation of 7-Chloro-9H-pyrimido[4,5-b]indole-based Glycogen Synthase Kinase-3β Inhibitors

by Stanislav Andreev, Tatu Pantsar, Francesco Ansideri, Mark Kudolo, Michael Forster, Dieter Schollmeyer, Stefan A. Laufer and Pierre Koch

Molecules 2019, 24(12), 2331; https://doi.org/10.3390/molecules24122331 - 25 Jun 2019

Cited by 11 | Viewed by 6026

Abstract

Glycogen synthase kinase-3β (GSK-3β) represents a relevant drug target for the treatment of neurodegenerative pathologies including Alzheimer’s disease. We herein report on the optimization of a novel class of GSK-3β inhibitors based on the tofacitinib-derived screen hit 3-((3R,4R)-3-((7-chloro-9H-pyrimido[4,5-b]indol-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (1). We synthesized a series of 19 novel 7-chloro-9H-pyrimido[4,5-b]indole-based derivatives and studied their structure–activity relationships with focus on the cyanoacetyl piperidine moiety. We unveiled the crucial role of the nitrile group and its importance for the activity of this compound series. A successful rigidization approach afforded 3-(3aRS,7aSR)-(1-(7-chloro-9H-pyrimido[4,5-b]indol-4-yl)octahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-propanenitrile (24), which displayed an IC₅₀ value of 130 nM on GSK-3β and was further characterized by its metabolic stability. Finally, we disclosed the putative binding modes of the most potent inhibitors within the ATP binding site of GSK-3β by 1 µs molecular dynamics simulations. Full article

(This article belongs to the Special Issue Kinase Inhibitors II)

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19 pages, 4659 KiB

Open AccessArticle

Ponatinib Inhibits Proliferation and Induces Apoptosis of Liver Cancer Cells, but Its Efficacy Is Compromised by Its Activation on PDK1/Akt/mTOR Signaling

by Chang Liu, Xiuli Mu, Xuan Wang, Chan Zhang, Lina Zhang, Baofeng Yu and Gongqin Sun

Molecules 2019, 24(7), 1363; https://doi.org/10.3390/molecules24071363 - 7 Apr 2019

Cited by 21 | Viewed by 4321

Abstract

Ponatinib is a multi-target protein tyrosine kinase inhibitor, and its effects on hepatocellular carcinoma cells have not been previously explored. In the present study, we investigated its effects on hepatocellular carcinoma cell growth and the underlying mechanisms. Toward SK-Hep-1 and SNU-423 cells, ponatinib induces apoptosis by upregulation of cleaved caspase-3 and -7 and promotes cell cycle arrest in the G1 phase by inhibiting CDK4/6/CyclinD1 complex and phosphorylation of retinoblastoma protein. It inhibits the growth-stimulating mitogen-activated protein (MAP) kinase pathway, the phosphorylation of Src on both negative and positive regulation sites, and Jak2 and Stat3 phosphorylation. Surprisingly, it also activates the PDK1, the protein kinase B (Akt), and the mechanistic target of rapamycin (mTOR) signaling pathway. Blocking mTOR signaling strongly sensitizes cells to inhibition by ponatinib and makes ponatinib a much more potent inhibitor of hepatocellular carcinoma cell proliferation. These findings demonstrate that ponatinib exerts both positive and negative effects on hepatocellular cell proliferation, and eliminating its growth-stimulating effects by drug combination or potentially by chemical medication can significantly improve its efficacy as an anti-cancer drug. Full article

(This article belongs to the Special Issue Kinase Inhibitors II)

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34 pages, 6132 KiB

Open AccessArticle

Design, Synthesis and Biological Evaluation of Isoxazole-Based CK1 Inhibitors Modified with Chiral Pyrrolidine Scaffolds

by Andreas Luxenburger, Dorian Schmidt, Chiara Ianes, Christian Pichlo, Marc Krüger, Thorsten von Drathen, Elena Brunstein, Graeme J. Gainsford, Ulrich Baumann, Uwe Knippschild and Christian Peifer

Molecules 2019, 24(5), 873; https://doi.org/10.3390/molecules24050873 - 1 Mar 2019

Cited by 13 | Viewed by 6525

Abstract

In this study, we report on the modification of a 3,4-diaryl-isoxazole-based CK1 inhibitor with chiral pyrrolidine scaffolds to develop potent and selective CK1 inhibitors. The pharmacophore of the lead structure was extended towards the ribose pocket of the adenosine triphosphate (ATP) binding site driven by structure-based drug design. For an upscale compatible multigram synthesis of the functionalized pyrrolidine scaffolds, we used a chiral pool synthetic route starting from methionine. Biological evaluation of key compounds in kinase and cellular assays revealed significant effects of the scaffolds towards activity and selectivity, however, the absolute configuration of the chiral moieties only exhibited a limited effect on inhibitory activity. X-ray crystallographic analysis of ligand-CK1δ complexes confirmed the expected binding mode of the 3,4-diaryl-isoxazole inhibitors. Surprisingly, the original compounds underwent spontaneous Pictet-Spengler cyclization with traces of formaldehyde during the co-crystallization process to form highly potent new ligands. Our data suggests chiral “ribose-like” pyrrolidine scaffolds have interesting potential for modifications of pharmacologically active compounds. Full article

(This article belongs to the Special Issue Kinase Inhibitors II)

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18 pages, 3208 KiB

Open AccessArticle

Drug Sensitivity Screening and Targeted Pathway Analysis Reveal a Multi-Driver Proliferative Mechanism and Suggest a Strategy of Combination Targeted Therapy for Colorectal Cancer Cells

by Jinyan Shen, Li Li, Tao Yang, Niuliang Cheng and Gongqin Sun

Molecules 2019, 24(3), 623; https://doi.org/10.3390/molecules24030623 - 11 Feb 2019

Cited by 9 | Viewed by 4315

Abstract

Treatment of colorectal cancer mostly relies on traditional therapeutic approaches, such as surgery and chemotherapy. Limited options of targeted therapy for colorectal cancer narrowly focus on blocking cancer-generic targets VEGFR and EGFR. Identifying the oncogenic drivers, understanding their contribution to proliferation, and finding inhibitors to block such drivers are the keys to developing targeted therapy for colorectal cancer. In this study, ten colorectal cancer cell lines were screened against a panel of protein kinase inhibitors blocking key oncogenic signaling pathways. The results show that four of the 10 cell lines did not respond to any kinase inhibitors significantly, the other six were mildly inhibited by AZD-6244, BMS-754807, and/or dasatinib. Mechanistic analyses demonstrate that these inhibitors independently block the MAP kinase pathway, IR/IGF-1R/AKT pathway, and Src kinases, suggesting a multi-driver nature of proliferative signaling in these cells. Most of these cell lines were potently and synergistically inhibited by pair-wise combinations of these drugs. Furthermore, seven of the 10 cell lines were inhibited by the triple combination of AZD-6244/BMS-754807/dasatinib with IC₅₀’s between 10 and 84 nM. These results suggest that combination targeted therapy may be an effective strategy against colorectal cancer. Full article

(This article belongs to the Special Issue Kinase Inhibitors II)

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15 pages, 10192 KiB

Open AccessArticle

Targeting of FGF-Signaling Re-Sensitizes Gastrointestinal Stromal Tumors (GIST) to Imatinib In Vitro and In Vivo

by Sergei Boichuk, Aigul Galembikova, Pavel Dunaev, Ekaterina Micheeva, Elena Valeeva, Maria Novikova, Natalya Khromova and Pavel Kopnin

Molecules 2018, 23(10), 2643; https://doi.org/10.3390/molecules23102643 - 15 Oct 2018

Cited by 20 | Viewed by 3705

Abstract

Dysregulation of the fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) signaling pathway is frequently observed in multiple human malignancies, and thus, therapeutic strategies targeting FGFs and FGFRs in human cancer are being extensively explored. We observed the activation of the FGF/FGFR-signaling pathway in imatinib (IM)-resistant gastrointestinal stromal tumor (GIST) cells. Furthermore, we found that the activation of FGFR signaling has a significant impact on IM resistance in GISTs in vitro. Next, we tested the efficacy of BGJ398, a potent and selective FGFR1–3 inhibitor, in xenograft models of GISTs exhibiting secondary IM resistance due to receptor-tyrosine kinase (RTK) switch (loss of c-KIT/gain of FGFR2a). Five to eight-week-old female nu/nu mice were subcutaneously inoculated into the flank areas with GIST T-1R cells. Mice were randomized as control (untreated), IM, BGJ398, or a combination and treated orally for 12 days. IM had a moderate effect on tumor size, thus revealing GIST resistance to IM. Similarly, a minor regression in tumor size was observed in BGJ398-treated mice. Strikingly, a 90% decrease in tumor size was observed in mice treated with a combination of IM and BGJ398. Treatment with BGJ398 and IM also induced major histopathologic changes according to a previously defined histopathologic response score and resulted in massive myxoid degeneration. This was associated with increased intratumoral apoptosis as detected by immunohistochemical staining for cleaved caspase-3 on day 5 of the treatment. Furthermore, treatment with BGJ398 and IM significantly reduced the proliferative activity of tumor cells as measured by positivity for Ki-67 staining. In conclusion, inhibition of FGFR signaling substantially inhibited the growth of IM-resistant GISTs in vitro and showed potent antitumor activity in an IM-resistant GIST model via the inhibition of proliferation, tumor growth, and the induction of apoptosis, thereby suggesting that patients with advanced and metastatic GISTs exhibiting IM resistance might benefit from therapeutic inhibition of FGFR signaling. Full article

(This article belongs to the Special Issue Kinase Inhibitors II)

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