Illuminating the druggable genome: Pathways to progress

Drug Discovery Today, Journal Year: 2023, Volume and Issue: 29(3), P. 103805 - 103805

Published: Oct. 27, 2023

There are ∼4500 genes within the 'druggable genome', subset of human genome that expresses proteins able to bind drug-like molecules, yet existing drugs only target a few hundred. A substantial druggable largely uncharacterized or understudied, with many falling G protein-coupled receptor (GPCR), ion channel, and kinase protein families. To improve scientific understanding these three understudied families, US National Institutes Health launched Illuminating Druggable Genome Program. Now, as it draws close, this review will lay out resources developed by program intended equip community tools necessary explore previously biology potential rapidly impact health.

Language: Английский

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Kinome state is predictive of cell viability in pancreatic cancer tumor and cancer-associated fibroblast cell lines

PeerJ, Journal Year: 2024, Volume and Issue: 12, P. e17797 - e17797

Published: Aug. 28, 2024

Numerous aspects of cellular signaling are regulated by the kinome-the network over 500 protein kinases that guides and modulates information transfer throughout cell. The key role played both individual assemblies organized into functional subnetworks leads to kinome dysregulation driving many diseases, particularly cancer. In case pancreatic ductal adenocarcinoma (PDAC), a variety associated pathways have been identified for their in establishment disease as well its progression. However, identification additional relevant therapeutic targets has slow is further confounded interactions between tumor surrounding microenvironment. this work, we attempt link state human kinome, or kinotype, with cell viability treated, patient-derived PDAC cancer-associated fibroblast lines. We applied classification models independent perturbation kinase inhibitor screen data, found inferred kinotype significant predictive relationship viability. find able identify set whose behavior response drive majority responses these lines, including understudied CSNK2A1/3, CAMKK2, PIP4K2C. next utilized predict new, clinical inhibitors were not present initial dataset model devlopment conducted validation confirmed accuracy models. These results suggest characterizing perturbed provides opportunity better understanding downstream phenotypes, providing insight broader design potential strategies PDAC.

Language: Английский

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Kinase Drug Discovery: Impact of Open Science and Artificial Intelligence

Molecular Pharmaceutics, Journal Year: 2024, Volume and Issue: 21(10), P. 4849 - 4859

Published: Sept. 6, 2024

Given their central role in signal transduction, protein kinases (PKs) were first implicated cancer development, caused by aberrant intracellular signaling events. Since then, PKs have become major targets different therapeutic areas. The preferred approach to intervention of PK-dependent diseases is the use small molecules inhibit catalytic phosphate group transfer activity. PK inhibitors (PKIs) are among most intensely pursued drug candidates, with currently 80 approved compounds and several hundred clinical trials. Following elucidation human kinome development robust expression systems high-throughput assays, large volumes PK/PKI data been produced industrial academic environments, more so than for many other pharmaceutical targets. In addition, hundreds X-ray structures complexes PKIs reported. Substantial amounts made publicly available part as a result open science initiatives. discovery further supported through incorporation approaches, including various specialized databases online resources. Compound activity wealth compared has also focal point application artificial intelligence (AI) research. Herein, we discuss interplay review exemplary studies that substantially contributed its profiling or analysis PKI promiscuity versus selectivity. We take close look at how AI approaches beginning impact light increasing orientation.

Language: Английский

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Assessing Darkness of the Human Kinome from a Medicinal Chemistry Perspective

Published: Aug. 22, 2024

In drug discovery, human protein kinases (PKs) represent one of the major target classes, due to their central role in cellular signaling, implication various diseases as a consequence deregulated and notable druggability. Individual PKs disease biology have been explored different degrees, giving rise heterogeneous functional knowledge associations across kinome. The U.S. National Institutes Health previously designated 162 understudied (“dark”) lipid kinases, lack annotations high-quality molecular probes for investigations. Given large volumes available PK inhibitors (PKIs) activity data, we systematically analyzed distribution PKIs associated data at confidence levels kinome distinguished between chemically explored, underexplored, unexplored PKs. analysis provides medicinal chemistry-centric view exploration further extends prior assessment dark

Language: Английский

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Assessing Darkness of the Human Kinome from a Medicinal Chemistry Perspective

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(19), P. 17919 - 17928

Published: Sept. 25, 2024

In drug discovery, human protein kinases (PKs) represent one of the major target classes due to their central role in cellular signaling, implication various diseases as a consequence deregulated and notable druggability. Individual PKs disease biology have been explored different degrees, giving rise heterogeneous functional knowledge associations across kinome. The U.S. National Institutes Health previously designated 162 understudied ("dark") lipid lack annotations high-quality molecular probes for investigations. Given large volumes available PK inhibitors (PKIs) activity data, we systematically analyzed distribution PKIs associated data at confidence levels kinome distinguished between chemically explored, underexplored, unexplored PKs. analysis provides medicinal chemistry-centric view exploration further extends prior assessment dark

Language: Английский

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