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

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

  • Chembiochem. 2024 Feb 13:e202300827. doi: 10.1002/cbic.202300827.
Cynthia V Pagba 1,  Amit K Gupta 1,  Kasuni Dilsha 2,  Parisa Sadrpour 3,  Jacob Jakubec 1,  Priyanka Prakash 1,  Dharini van der Hoeven 4,  Kwang-Jin Cho 3,  Scott Gilbertson 2,  Alemayehu A Gorfe 1 5
Affiliations

Affiliations

  • 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.
PMID: 38349283 DOI: 10.1002/cbic.202300827
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.

Keywords

Ras protein; anticancer drug; inhibitor; signal transduction.

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