Journal article
KRAS Inhibitor that Simultaneously Inhibits Nucleotide Exchange Activity and Effector Engagement
ACS bio & med chem au, Vol.2(6), pp.617-626
12/21/2022
DOI: 10.1021/acsbiomedchemau.2c00045
PMCID: PMC10125367
PMID: 37101428
Abstract
We describe a small molecule ligand ACA-14 (2-hydroxy-5-{[(2-phenyl-cyclopropyl) carbonyl] amino} benzoic acid) as an initial lead for the development of direct inhibitors of KRAS, a notoriously difficult anticancer drug target. We show that the compound binds to KRAS near the switch regions with affinities in the low micromolar range and exerts different effects on KRAS interactions with binding partners. Specifically, ACA-14 impedes the interaction of KRAS with its effector Raf and reduces both intrinsic and SOS-mediated nucleotide exchange rates. Likely as a result of these effects, ACA-14 inhibits signal transduction through the MAPK pathway in cells expressing mutant KRAS and inhibits the growth of pancreatic and colon cancer cells harboring mutant KRAS. We thus propose compound ACA-14 as a useful initial lead for the development of broad-acting inhibitors that target multiple KRAS mutants and simultaneously deplete the fraction of GTP-loaded KRAS while abrogating the effector-binding ability of the already GTP-loaded fraction.
Details
- Title: Subtitle
- KRAS Inhibitor that Simultaneously Inhibits Nucleotide Exchange Activity and Effector Engagement
- Creators
- CynthiaV Pagba - Univ Texas Hlth Sci Ctr, McGovern Med Sch, Dept Integrat Biol & Pharmacol, Houston, TX 77030 USAAmit K. Gupta - The University of Texas Health Science Center at HoustonAli K Naji - The University of Texas Health Science Center at HoustonDharini van der Hoeven - The University of Texas Health Science Center at HoustonKelly Churion - Texas A&M Health Science CenterXiaowen Liang - The University of Texas Health Science Center at HoustonJacob Jakubec - The University of Texas Health Science Center at HoustonMagnus Hook - Texas A&M Health Science CenterYan Zuo - The University of Texas Health Science Center at HoustonMarisela Martinez de Kraatz - Univ Texas Hlth Sci Ctr, McGovern Med Sch, Dept Integrat Biol & Pharmacol, Houston, TX 77030 USAJeffrey A. Frost - The University of Texas MD Anderson Cancer CenterAlemayehu A. Gorfe - The University of Texas MD Anderson Cancer Center
- Resource Type
- Journal article
- Publication Details
- ACS bio & med chem au, Vol.2(6), pp.617-626
- DOI
- 10.1021/acsbiomedchemau.2c00045
- PMID
- 37101428
- PMCID
- PMC10125367
- NLM abbreviation
- ACS Bio Med Chem Au
- ISSN
- 2694-2437
- eISSN
- 2694-2437
- Publisher
- Amer Chemical Soc
- Number of pages
- 10
- Grant note
- W81XWH-20-1-0004 / Department of Defense Breast Cancer Research Program; United States Department of Defense DP150093; RP190366 / Cancer Prevention and Research Institute of Texas (CPRIT); Cancer Prevention & Research Institute of Texas RP170593 / Keck Center Computational Cancer Biology Training Program (CCBTP) of the Gulf Coast Consortia (CPRIT)
- Language
- English
- Date published
- 12/21/2022
- Academic Unit
- Oral Pathology, Radiology and Medicine; Dentistry Administration
- Record Identifier
- 9985157545402771
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