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

Cynthia V Pagba; Amit K Gupta; Kasuni Dilsha; Parisa Sadrpour; Jacob Jakubec; Priyanka Prakash; Dharini van der Hoeven; Kwang-Jin Cho; Scott Gilbertson; Alemayehu A Gorfe

doi:10.1002/cbic.202300827

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

Journal article

Peer reviewed

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

Cynthia V Pagba, Amit K Gupta, Kasuni Dilsha, Parisa Sadrpour, Jacob Jakubec, Priyanka Prakash, Dharini van der Hoeven, Kwang-Jin Cho, Scott Gilbertson and Alemayehu A Gorfe

Chembiochem : a European journal of chemical biology, Vol.25(7), pp.e202300827-n/a

04/02/2024

DOI: 10.1002/cbic.202300827

PMID: 38349283

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Abstract

We 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.

Antineoplastic Agents - pharmacology

Cell Line, Tumor

Mutation

Proto-Oncogene Proteins p21(ras) - genetics

Signal Transduction

Details

Title: Subtitle: Biophysical and Biochemical Characterization of Structurally Diverse Small Molecule Hits for KRAS Inhibition
Creators: Cynthia V Pagba - The University of Texas Health Science Center
Amit K Gupta - The University of Texas Health Science Center at Houston
Kasuni Dilsha - University of Houston
Parisa Sadrpour - Wright State University
Jacob Jakubec - The University of Texas Health Science Center at Houston
Priyanka Prakash - The University of Texas Health Science Center at Houston
Dharini van der Hoeven - The University of Texas Health Science Center at Houston
Kwang-Jin Cho - Wright State University
Scott Gilbertson - University of Houston
Alemayehu A Gorfe - The University of Texas MD Anderson Cancer Center
Resource Type: Journal article
Publication Details: Chembiochem : a European journal of chemical biology, Vol.25(7), pp.e202300827-n/a
DOI: 10.1002/cbic.202300827
PMID: 38349283
ISSN: 1439-4227
eISSN: 1439-7633
Grant note: RP190366 / Cancer Prevention and Research Institute of Texas Northeastern University UTHealth NIH RAS Initiative
Language: English
Date published: 04/02/2024
Academic Unit: Oral Pathology, Radiology and Medicine; Dentistry Administration
Record Identifier: 9985157544702771

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