Biophysical and Biochemical Characterization of Structurally Diverse Small Molecule Hits for KRAS Inhibition

Author:

Pagba Cynthia V.1ORCID,Gupta Amit K.1,Dilsha Kasuni2,Sadrpour Parisa3,Jakubec Jacob1,Prakash Priyanka1,van der Hoeven Dharini4,Cho Kwang‐Jin3,Gilbertson Scott2,Gorfe Alemayehu A.15ORCID

Affiliation:

1. Department of Integrative Biology and Pharmacology, McGovern Medical School The University of Texas Health Science Center at Houston 6431 Fannin St. Houston Texas 77030 USA

2. Department of Chemistry University of Houston 3585 Cullen Blvd. Houston TX 77204 USA

3. Department of Biochemistry and Molecular Biology Wright State University 3640 Colonel Glenn Hwy Dayton OH 45435 USA

4. Department of Diagnostic and Biomedical Sciences, School of Dentistry The University of Texas Health Science Center at Houston 7500 Cambridge St. Houston Texas 77030 USA

5. Biochemistry and Cell Biology Program & Therapeutics and Pharmacology Program UTHealth MD Anderson Cancer Center Graduate School of Biomedical Sciences, Houston 6431 Fannin St. Houston Texas 77030 USA

Abstract

AbstractWe describe six compounds as early hits for the development of direct inhibitors of KRAS, an important anticancer drug target. We show that these compounds bind to KRAS with affinities in the low micromolar range and exert different effects on its interactions with binding partners. Some of the compounds exhibit selective binding to the activated form of KRAS and inhibit signal transduction through both the MAPK or the phosphatidylinositide 3‐kinase PI3K‐protein kinase B (AKT) pathway in cells expressing mutant KRAS. Most inhibit intrinsic and/or SOS‐mediated KRAS activation while others inhibit RAS‐effector interaction. We propose these compounds as starting points for the development of non‐covalent allosteric KRAS inhibitors.

Funder

University of Texas Health Science Center at Houston

Northeastern University

Cancer Prevention and Research Institute of Texas

Publisher

Wiley

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