Structural features of the protein kinase domain and targeted binding by small-molecule inhibitors

Arter, Christopher; Trask, Luke; Ward, Sarah; Yeoh, Sharon; Bayliss, Richard

doi:10.1016/j.jbc.2022.102247

Cited by 57 publications

(57 citation statements)

References 122 publications

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“…AZ191 (5). AZ191 was identified as an inhibitor displaying a 10-fold selectivity for DYRK1B over DYRK1A (IC 50 = 17 and 88 nM, respectively).…”

Section: ■ Resultssupporting

confidence: 83%

“…The most DYRKselective compounds were JH-XIV-68-3 (15) and F-DANDY (11). A few noticeably selective compounds were the CLK4selective MU1210 (49) and T3 (55), the DYRK1A-selective compound 5j (7) and JH-XVII-10 ( 16), the DYRK1B-selective AZ191 (5), the DYRK1A/DYRK1B-selective JH-XIV-68-3 (15) and F-DANDY (11), and the DYRK2-selective compound C17 (37) and LDN-192960 (46).…”

Section: ■ Resultsmentioning

confidence: 99%

“…A derivative, compound 12g, was described recently as very potent on CLK1, CLK2, and CLK4 (IC 50 = 4, 28, 55 nM, respectively) but poorly active on CLK3 and DYRK1A (IC 50 = 339 and 3940 nM, respectively). 115 Desmethylbellidifolin (DMB) (1,3,5,8-tetrahydroxyxanthone) (40). DMB is a natural xanthone extracted from Gentianella acuta, an antidiarrhea drug derived from traditional Mongolian herbal medicine.…”

Section: ■ Resultsmentioning

confidence: 99%

“…Almost 70 years have elapsed since the discovery of protein kinases by Edmond H. Fischer and Edwin G. Krebs. , Initially focused on fundamental functions in cell signaling and on structural aspects, the field of protein kinases and protein phosphorylation has expanded exponentially into more clinically applied areas through the search and characterization of specific and potent pharmacological inhibitors. − By early 2023, 72 kinase inhibitors had reached the pharmaceutical market, mostly as anticancer drugs …”

Section: Introductionmentioning

confidence: 99%

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Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases

et al. 2023

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Dual-specificity, tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) play a large variety of cellular functions and are involved in several diseases (cognitive disorders, diabetes, cancers, etc.). There is, thus, growing interest in pharmacological inhibitors as chemical probes and potential drug candidates. This study presents an unbiased evaluation of the kinase inhibitory activity of a library of 56 reported DYRK/CLK inhibitors on the basis of comparative, side-by-side, catalytic activity assays on a panel of 12 recombinant human kinases, enzyme kinetics (residence time and K d), in-cell inhibition of Thr-212-Tau phosphorylation, and cytotoxicity. The 26 most active inhibitors were modeled in the crystal structure of DYRK1A. The results show a rather large diversity of potencies and selectivities among the reported inhibitors and emphasize the difficulties to avoid “off-targets” in this area of the kinome. The use of a panel of DYRKs/CLKs inhibitors is suggested to analyze the functions of these kinases in cellular processes.

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“…AZ191 (5). AZ191 was identified as an inhibitor displaying a 10-fold selectivity for DYRK1B over DYRK1A (IC 50 = 17 and 88 nM, respectively).…”

Section: ■ Resultssupporting

confidence: 83%

Section: ■ Resultsmentioning

confidence: 99%

Section: ■ Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases

et al. 2023

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“…It is worth noting that there is a high level of structural similarity between protein kinases, as all of them accept ATP as a substrate [ 9 ]. This, in most cases, results in the non-specificity of a particular inhibitor for its main target.…”

Section: Introductionmentioning

confidence: 99%

Novel Phthalic-Based Anticancer Tyrosine Kinase Inhibitors: Design, Synthesis and Biological Activity

Kalinichenko

Faryna

Bozhok

et al. 2023

CIMB

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In this work, fragments of isophthalic and terephthalic acids are proposed as a structural scaffold to develop potential inhibitors of protein kinases. Novel isophthalic and terephthalic acid derivatives were designed as type-2 protein kinase inhibitors, synthesized and subjected to physicochemical characterization. The screening of their cytotoxic actions against a panel of cell lines derived from different types of tumors (liver, renal, breast and lung carcinomas, as well as chronic myelogenous and promyelocytic leukemia) and normal human B lymphocyte, for the sake of comparison, was performed. Compound 5 showed the highest inhibitory activity against four cancer cell lines, K562, HL-60, MCF-7 and HepG2 (IC50 = 3.42, 7.04, 4.91 and 8.84 µM, respectively). Isophthalic derivative 9 revealed a high potency against EGFR and HER2, at the levels of 90% and 64%, respectively, being comparable to lapatinib at 10 µM. In general, tumor cell cultures were more sensitive to isophthalic acid derivatives than to terephthalic acid ones. In cell cycle studies, isophthalic analogue 5 showed a pronounced dose-dependent effect, and with the increase in its concentration up to 10.0 µM, the number of living cells decreased to 38.66%, while necrosis reached 16.38%. The considered isophthalic compounds had a similar docking performance to that of sorafenib against the VEGFR-2 (PDB id: 4asd, 3wze). The correct binding of compounds 11 and 14 with VEGFR-2 was validated using MD simulations and MM-GPSA calculations.

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Hit discovery of novel 2‐phenyl‐substituted 4‐amino–6,7‐dihydro‐5H‐cyclopenta[d]pyrimidines as potential anti‐glioblastoma therapeutics: Design, synthesis, biological evaluation, and computational screening

Khairnar

Sonawane

Cheke

et al. 2023

Drug Development Research

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Glioblastoma multiforme (GBM) is a highly‐aggressive, dreadful disease with poor prognosis and disappointing clinical success. There is an unmet medical need of molecularly‐targeted therapeutics for GBM treatment. In the present work, a series of novel 2‐phenyl‐substituted 4‐amino–6,7‐dihydro‐5H‐cyclopenta[d]pyrimidines was designed, synthesized, purified, characterized, and evaluated for cytotoxicity against glioblastoma cell line U87‐MG. The design process (virtual library enumeration around the core, physicochemical and molecular property prediction/calculation of the designs, filtering the undesirable ones, and the diversity analyses of the lead‐like designs), was carefully curated so as to obtain a set of structurally‐diverse, novel molecules (total 20), with a particular focus on the relatively unexplored core structure, 6,7‐dihydro‐5H‐cyclopenta[d]pyrimidine. The preliminary screening was done using MTT assay at 10 and 100 μM concentrations of the title compounds F1−F20 and positive control cisplatin, which yielded six hits (% inhibition at 10 μM: ~50%)—F2, F3, F5, F7, F15, and F20, which were taken up for IC50 determination. The top hits F2 and F7 (IC50 < 10 μM) were further used for computational studies such as target prediction, followed by their molecular docking in the binding sites of the top‐3 predicted targets (epidermal growth factor receptor kinase domain, cyclin‐dependent kinase 2 [CDK2]) /cyclin E, and anaplastic lymphoma kinase [ALK]). The docking pose analyses revealed interesting trends. The relatively planar core structure, presence of favorable hinge‐binding substructures, basic groups, all added up, and culminated in appreciable cytotoxicity against GBM cell line.

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Structural features of the protein kinase domain and targeted binding by small-molecule inhibitors

Cited by 57 publications

References 122 publications

Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases

Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases

Novel Phthalic-Based Anticancer Tyrosine Kinase Inhibitors: Design, Synthesis and Biological Activity

Hit discovery of novel 2‐phenyl‐substituted 4‐amino–6,7‐dihydro‐5H‐cyclopenta[d]pyrimidines as potential anti‐glioblastoma therapeutics: Design, synthesis, biological evaluation, and computational screening

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