Discovery of High-Affinity Noncovalent Allosteric KRAS Inhibitors That Disrupt Effector Binding
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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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KRAS protein is a featureless, nearly spherical structure with no obvious binding sites, making it difficult to synthesize compounds that can effectively target and inhibit its activity.
“In summary, KRAS protein is a featureless, nearly spherical structure with no obvious binding sites, making it difficult to synthesize compounds that can effectively target and inhibit its activity.45”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [45]
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- Authors
- McCarthy, M. J., Pagba, C. V., Prakash, P., Naji, A. K., van der Hoeven, D., Liang, H., Gupta, A. K., Zhou, Y., Cho, K.-J., Hancock, J. F., & Gorfe, A. A.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- The University of Texas Health Science Center at Houston (US)
- The University of Texas Health Science Center at Houston , , Cambridge Street , , ,
- The University of Texas Health Science Center at Houston , , 6431 Fannin Street , , ,
- Wright State University (US)
- Corresponding author
- Gorfe, Alemayehu A.
- ORCID
- Venue
- ACS Omega
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-02-08
- Volume
- 4
- Issue
- 2
- Pages
- 2921-2930
- ISSN
- 2470-1343 (ISSN-L)
- PMC
- PMC6396121
- OpenAlex
- W2912092319
- Cited by
- 90
- References
- 54
- Citations by year
- 2026: 10 · 2025: 7 · 2024: 7 · 2023: 12 · 2022: 15 · 2021: 10 · 2020: 14 · 2019: 14
- FWCI
- 4.38
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- ACS Omega (publishedVersion, other-oa)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Cancer Institute (R00CA188593)
- Cancer Prevention and Research Institute of Texas (DP150093)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- KRAS, allosteric inhibitors, non-covalent inhibitors, pyrazolopyrimidines, effector binding, GTPase, oncogenes, structure-based drug design, switch regions, cancer cell growth, small molecule inhibitors
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