Inhibition of Nonfunctional Ras

Overview

Journal Cell Chem Biol

Publisher Cell Press

Specialty Biochemistry

Date 2021 Jan 13

PMID 33440168

Citations 14

Authors

Ruth Nussinov

Hyunbum Jang

Attila Gursoy

Ozlem Keskin

Vadim Gaponenko

Affiliations

Soon will be listed here.

Abstract

Intuitively, functional states should be targeted; not nonfunctional ones. So why could drugging the inactive K-Ras4Bwork-but drugging the inactive kinase will likely not? The reason is the distinct oncogenic mechanisms. Kinase driver mutations work by stabilizing the active state and/or destabilizing the inactive state. Either way, oncogenic kinases are mostly in the active state. Ras driver mutations work by quelling its deactivation mechanisms, GTP hydrolysis, and nucleotide exchange. Covalent inhibitors that bind to the inactive GDP-bound K-Ras4B conformation can thus work. By contrast, in kinases, allosteric inhibitors work by altering the active-site conformation to favor orthosteric drugs. From the translational standpoint this distinction is vital: it expedites effective pharmaceutical development and extends the drug classification based on the mechanism of action. Collectively, here we postulate that drug action relates to blocking the mechanism of activation, not to whether the protein is in the active or inactive state.

Citing Articles

CDK2 and CDK4: Cell Cycle Functions Evolve Distinct, Catalysis-Competent Conformations, Offering Drug Targets.

Zhang W, Liu Y, Jang H, Nussinov R JACS Au. 2024; 4(5):1911-1927.

PMID: 38818077 PMC: 11134382. DOI: 10.1021/jacsau.4c00138.

AlphaFold, allosteric, and orthosteric drug discovery: Ways forward.

Nussinov R, Zhang M, Liu Y, Jang H Drug Discov Today. 2023; 28(6):103551.

PMID: 36907321 PMC: 10238671. DOI: 10.1016/j.drudis.2023.103551.

Strategy toward Kinase-Selective Drug Discovery.

Zhang M, Liu Y, Jang H, Nussinov R J Chem Theory Comput. 2023; 19(5):1615-1628.

PMID: 36815703 PMC: 10018734. DOI: 10.1021/acs.jctc.2c01171.

A New View of Activating Mutations in Cancer.

Nussinov R, Tsai C, Jang H Cancer Res. 2022; 82(22):4114-4123.

PMID: 36069825 PMC: 9664134. DOI: 10.1158/0008-5472.CAN-22-2125.

Allosteric regulation of autoinhibition and activation of c-Abl.

Liu Y, Zhang M, Tsai C, Jang H, Nussinov R Comput Struct Biotechnol J. 2022; 20:4257-4270.

PMID: 36051879 PMC: 9399898. DOI: 10.1016/j.csbj.2022.08.014.

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