Journal article
Discovery of High-Affinity Noncovalent Allosteric KRAS Inhibitors That Disrupt Effector Binding
ACS omega, Vol.4(2), pp.2921-2930
02/28/2019
DOI: 10.1021/acsomega.8b03308
PMID: 30842983
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.
Details
- Title: Subtitle
- Discovery of High-Affinity Noncovalent Allosteric KRAS Inhibitors That Disrupt Effector Binding
- Creators
- Michael J. McCarthy - The University of Texas MD Anderson Cancer CenterCynthia V. Pagba - The University of Texas Health Science Center at HoustonPriyanka Prakash - 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 HoustonHong Liang - Univ Texas Hlth Sci Ctr Houston, Dept Integrat Biol & Pharmacol, McGovern Med Sch, 6431 Fannin St, Houston, TX 77030 USAAmit K. Gupta - The University of Texas Health Science Center at HoustonYong Zhou - The University of Texas MD Anderson Cancer CenterKwang-Jin Cho - Wright State UniversityJohn F. Hancock - 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 omega, Vol.4(2), pp.2921-2930
- DOI
- 10.1021/acsomega.8b03308
- PMID
- 30842983
- ISSN
- 2470-1343
- eISSN
- 2470-1343
- Publisher
- Amer Chemical Soc
- Number of pages
- 10
- Grant note
- R00CA188593 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA DP150093 / Cancer Prevention and Research Institute of Texas (CPRIT) RP170593 / Keck Center Computational Cancer Biology Training Program (CCBTP) of the Gulf Coast Consortia (CPRIT grant) R00CA188593 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Language
- English
- Date published
- 02/28/2019
- Academic Unit
- Oral Pathology, Radiology and Medicine; Dentistry Administration
- Record Identifier
- 9985157545602771