Electrophilic Fragment-Based Design of Reversible Covalent Kinase Inhibitors

Journal of the American Chemical Society, Journal Year: 2013, Volume and Issue: 135(14), P. 5298 - 5301

Published: March 29, 2013

Fragment-based ligand design and covalent targeting of noncatalytic cysteines have been employed to develop potent selective kinase inhibitors. Here, we combine these approaches, starting with a panel low-molecular-weight, heteroaryl-susbstituted cyanoacrylamides, which previously shown form reversible bonds cysteine thiols. Using this strategy, identify electrophilic fragments sufficient efficiency selectivity serve as points for the first reported inhibitors MSK1 C-terminal domain. Guided by X-ray co-crystal structures, indazole fragment 1 was elaborated afford 12 (RMM-46), inhibitor that exhibits high MSK/RSK-family kinases. At nanomolar concentrations, blocked activation cellular MSK RSK, well downstream phosphorylation critical transcription factor, CREB.

Language: Английский

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Discovery of Potent VEGFR-2 Inhibitors based on Furopyrimidine and Thienopyrimidne Scaffolds as Cancer Targeting Agents

Scientific Reports, Journal Year: 2016, Volume and Issue: 6(1)

Published: April 15, 2016

Abstract Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in cancer angiogenesis. In this study, series of novel furo[2,3- d ]pyrimidine and thieno[2,3- based-derivatives were designed synthesized as VEGFR-2 inhibitors, accordance to the structure activity relationship (SAR) studies known type II inhibitors. The compounds evaluated for their ability vitro inhibit kinase enzyme. Seven (15b, 16c, 16e, 21a, 21b, 21c 21e) demonstrated highly potent dose-related inhibition with IC 50 values nanomolar range, which (21b, exhibited 33.4, 47.0 21 nM respectively. Moreover, ]pyrimidine-based derivative (15b) showed strongest human umbilical vein cells (HUVEC) proliferation 99.5% at 10 μM concentration. Consistent our findings, ( 21b orally administered 5 mg/kg/day 8 consecutive days anticancer Erhlich ascites carcinoma (EAC) solid tumor murine model. Such blunted angiogenesis EAC evidenced by reduced percent microvessel via decreasing phosphorylation subsequent induction apoptotic machinery. Furthermore, Miles vascular permeability assay confirmed antiangiogenic effects vivo . Intriguingly, such no obvious toxicity.

Language: Английский

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Novel 2-chloro-4-anilino-quinazoline derivatives as EGFR and VEGFR-2 dual inhibitors

European Journal of Medicinal Chemistry, Journal Year: 2013, Volume and Issue: 71, P. 1 - 14

Published: Oct. 31, 2013

Language: Английский

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1-Piperazinylphthalazines as potential VEGFR-2 inhibitors and anticancer agents: Synthesis and in vitro biological evaluation

European Journal of Medicinal Chemistry, Journal Year: 2015, Volume and Issue: 107, P. 165 - 179

Published: Nov. 6, 2015

Language: Английский

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Design, synthesis, molecular docking and cytotoxic evaluation of novel 2-furybenzimidazoles as VEGFR-2 inhibitors

European Journal of Medicinal Chemistry, Journal Year: 2017, Volume and Issue: 136, P. 315 - 329

Published: April 26, 2017

Language: Английский

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