The role of ligand efficiency metrics in drug discovery

Nature Reviews Drug Discovery, Journal Year: 2014, Volume and Issue: 13(2), P. 105 - 121

Published: Jan. 31, 2014

Language: Английский

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FDA-approved small-molecule kinase inhibitors

Trends in Pharmacological Sciences, Journal Year: 2015, Volume and Issue: 36(7), P. 422 - 439

Published: May 12, 2015

Language: Английский

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Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes

Pharmacological Research, Journal Year: 2015, Volume and Issue: 103, P. 26 - 48

Published: Nov. 4, 2015

Language: Английский

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Renal cell carcinoma

BMJ, Journal Year: 2014, Volume and Issue: 349(nov10 11), P. g4797 - g4797

Published: Nov. 10, 2014

The treatment of renal cell carcinoma (RCC) has changed greatly over the past 15 years. Progress in surgical management primary tumor and increased understanding molecular biology genomics disease have led to development new therapeutic agents. owing realization that clean margins around lesion are sufficient prevent local recurrence, as well more sophisticated tools techniques increase safety partial nephrectomy. advanced altered even dramatically a result agents target vasculature or attenuate activation intracellular oncogenic pathways. This review summarizes data from prospective randomized phase III studies on systemic RCC, provides an up date summary histology, genomics, staging, prognosis RCC. It describes offers overview form mainstay for disease. concludes with introduction exciting class immunomodulatory currently clinical trials may basis approach patients

Language: Английский

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Indoles as therapeutics of interest in medicinal chemistry: Bird's eye view

European Journal of Medicinal Chemistry, Journal Year: 2017, Volume and Issue: 134, P. 159 - 184

Published: April 5, 2017

Language: Английский

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Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor

New England Journal of Medicine, Journal Year: 2015, Volume and Issue: 373(5), P. 428 - 437

Published: July 29, 2015

Expression of the colony-stimulating factor 1 (CSF1) gene is elevated in most tenosynovial giant-cell tumors. This observation has led to discovery and clinical development therapy targeting CSF1 receptor (CSF1R).Using x-ray co-crystallography guide our drug-discovery research, we generated a potent, selective CSF1R inhibitor, PLX3397, that traps kinase autoinhibited conformation. We then conducted multicenter, phase trial two parts analyze this compound. In first part, evaluated escalations dose PLX3397 was administered orally patients with solid tumors (dose-escalation study). second at chosen 2 an extension cohort (extension Pharmacokinetic tumor responses enrolled were assessed, situ hybridization performed confirm mechanism action pattern expression consistent pathological features tumor.A total 41 dose-escalation study, additional 23 study. The 1000 mg per day. 12 had partial response 7 stable disease. Responses usually occurred within 4 months treatment, median duration exceeded 8 months. common adverse events included fatigue, change hair color, nausea, dysgeusia, periorbital edema; rarely discontinuation treatment.Treatment resulted prolonged regression volume patients. (Funded by Plexxikon; ClinicalTrials.gov number, NCT01004861.).

Language: Английский

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Spectrum and Degree of CDK Drug Interactions Predicts Clinical Performance

Molecular Cancer Therapeutics, Journal Year: 2016, Volume and Issue: 15(10), P. 2273 - 2281

Published: Aug. 6, 2016

Abstract Therapeutically targeting aberrant intracellular kinase signaling is attractive from a biological perspective but drug development often hindered by toxicities and inadequate efficacy. Predicting behaviors using cellular animal models confounded redundant activities, lack of unique substrates, cell-specific networks. Cyclin-dependent (CDK) drugs exemplify this phenomenon because they are reported to target common processes yet have distinct clinical activities. Tumor cell studies ATP-competitive CDK (dinaciclib, AG-024322, abemaciclib, palbociclib, ribociclib) indicate similar pharmacology while analyses in untransformed cells illuminates significant differences. To resolve apparent disconnect, described at the molecular level. Nonkinase binding kinome interaction analysis (recombinant endogenous kinases) reveal that proteins outside family appear little role dinaciclib/palbociclib/ribociclib pharmacology, may contribute for confounds AG-024322 analysis. CDK2 CDK6 cocrystal structures with identify interactions responsible potency selectivity. Efficient hinge architecture CDKs enables selectivity toward most human kinome. Selectivity between members achieved through nonconserved elements ATP-binding pocket. Integrating exposures into predicts both palbociclib ribociclib CDK4/6 inhibitors, abemaciclib inhibits CDK4/6/9, dinaciclib broad-spectrum inhibitor (CDK2/3/4/6/9). Understanding components also facilitates rational design future generations kinase-directed drugs. Mol Cancer Ther; 15(10); 2273–81. ©2016 AACR.

Language: Английский

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Deep Docking: A Deep Learning Platform for Augmentation of Structure Based Drug Discovery

ACS Central Science, Journal Year: 2020, Volume and Issue: 6(6), P. 939 - 949

Published: May 19, 2020

Drug discovery is a rigorous process that requires billion dollars of investments and decades research to bring molecule "from bench bedside". While virtual docking can significantly accelerate the drug discovery, it ultimately lags current rate expansion chemical databases already exceed billions molecular records. This recent surge small molecules availability presents great opportunities, but also demands much faster screening protocols. In order address this challenge, we herein introduce Deep Docking (DD), novel deep learning platform suitable for structures in rapid, yet accurate fashion. The DD approach utilizes quantitative structure–activity relationship (QSAR) models trained on scores subsets library approximate outcome unprocessed entries and, therefore, remove unfavorable an iterative manner. use methodology conjunction with FRED program allowed rapid calculation 1.36 from ZINC15 against 12 prominent target proteins demonstrated up 100-fold data reduction 6000-fold enrichment high scoring (without notable loss favorably docked entities). protocol readily be used any was made publicly available.

Language: Английский

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Rho Kinase (ROCK) Inhibitors and Their Therapeutic Potential

Journal of Medicinal Chemistry, Journal Year: 2015, Volume and Issue: 59(6), P. 2269 - 2300

Published: Oct. 21, 2015

Rho kinases (ROCKs) belong to the serine-threonine family, inhibition of which affects function many downstream substrates. As such, ROCK inhibitors have potential therapeutic applicability in a wide variety pathological conditions including asthma, cancer, erectile dysfunction, glaucoma, insulin resistance, kidney failure, neuronal degeneration, and osteoporosis. To date, two been approved for clinical use Japan (fasudil ripasudil) one China (fasudil). In 1995 fasudil was treatment cerebral vasospasm, more recently, ripasudil glaucoma 2014. this Perspective, we present comprehensive review physiological biological functions ROCK, properties development over 170 as well their potential, current status, future considerations.

Language: Английский

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Molecular Bases of VEGFR-2-Mediated Physiological Function and Pathological Role

Frontiers in Cell and Developmental Biology, Journal Year: 2020, Volume and Issue: 8

Published: Nov. 16, 2020

The VEGF/VEGFR-2 system participates in vasculogenesi and angiogenesis. Angiogenesis, as an important mechanism many physiological pathological processes, is involved endothelial cell proliferation, migration, survival, leads to further tubulogenesis, finally promotes formation of vessels. This series signaling cascade pathways are precisely mediated by system. VEGF binding the IgD2 IgD3 VEGFR-2 induces dimerization receptor, subsequently activation trans-autophosphorylation tyrosine kinase, then initiation intracellular cascades, VEGF-activated stimulates mediates variety transduction, biological responses, processes angiogenesis, which several crucial phosphorylated sites Tyr801, Try951, Try1175, Try1214 domains mediate key including PLCγ-PKC, TSAd-Src-PI3K-Akt, SHB-FAK-paxillin, SHB-PI3K-Akt, NCK-p38-MAPKAPK2/3 pathways. Based on molecular structure VEGFR-2, strategy VEGFR-2-targeted therapy should be considered employ treatment this system-associated diseases blocking pathway, inhibiting gene expression, destroying vascular cells expressing VEGFR-2.

Language: Английский

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