2. Academic Validation
  3. Discovery of High-Affinity Noncovalent Allosteric KRAS Inhibitors That Disrupt Effector Binding

Discovery of High-Affinity Noncovalent Allosteric KRAS Inhibitors That Disrupt Effector Binding

  • ACS Omega. 2019 Feb 28;4(2):2921-2930. doi: 10.1021/acsomega.8b03308.
Michael J McCarthy 1 2,  Cynthia V Pagba 1,  Priyanka Prakash 1,  Ali K Naji 3,  Dharini van der Hoeven 3,  Hong Liang 1,  Amit K Gupta 1,  Yong Zhou 1 2,  Kwang-Jin Cho 4,  John F Hancock 1 2,  Alemayehu A Gorfe 1 2
Affiliations

Affiliations

  • 1 Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, Texas 77030, United States.
  • 2 Biochemistry and Cell Biology Program, UTHealth MD Anderson Cancer Center Graduate School of Biomedical Sciences, 6431 Fannin Street, Houston, Texas 77030, United States.
  • 3 Department of Diagnostic and Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Cambridge Street, Houston, Texas 7500, United States.
  • 4 Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio 45435, United States.
PMID: 30842983 DOI: 10.1021/acsomega.8b03308
Abstract

Approximately 15% of all human tumors harbor mutant KRAS, a membrane-associated small GTPase and notorious oncogene. Mutations that render KRAS constitutively active will lead to uncontrolled cell growth and Cancer. However, despite aggressive efforts in recent years, there are no drugs on the market that directly target KRAS and inhibit its aberrant functions. In the current work, we combined structure-based design with a battery of cell and biophysical assays to discover a novel pyrazolopyrimidine-based allosteric KRAS inhibitor that binds to activated KRAS with sub-micromolar affinity and disrupts effector binding, thereby inhibiting KRAS signaling and Cancer cell growth. These results show that pyrazolopyrimidine-based compounds may represent a first-in-class allosteric noncovalent inhibitors of KRAS. Moreover, by studying two of its analogues, we identified key chemical features of the compound that interact with a set of specific residues at the switch regions of KRAS and play critical roles for its high-affinity binding and unique mode of action, thus providing a blueprint for future optimization efforts.

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