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Discovery of High-Affinity Noncovalent Allosteric KRAS Inhibitors That Disrupt Effector Binding
Michael J McCarthy1,2, Cynthia V Pagba1, Priyanka Prakash1
1Department 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.
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.
Insights
Researchers discovered a novel pyrazolopyrimidine compound that acts as an allosteric inhibitor for the KRAS oncogene. This breakthrough offers a potential new therapeutic strategy for KRAS-driven cancers by blocking tumor cell growth.
Area of Science:
- Oncology
- Molecular Biology
- Medicinal Chemistry
Background:
- Mutant KRAS is implicated in approximately 15% of human tumors, driving uncontrolled cell proliferation.
- Despite its oncogenic role, direct KRAS inhibitors remain elusive, posing a significant challenge in cancer therapy.
Purpose of the Study:
- To discover and characterize novel allosteric inhibitors targeting the KRAS oncogene.
- To identify chemical features crucial for high-affinity KRAS inhibition and explore therapeutic potential.
Main Methods:
- Employed structure-based design principles.
- Utilized a comprehensive suite of cell-based and biophysical assays.
- Investigated pyrazolopyrimidine derivatives and their analogues.
Main Results:
- Identified a novel pyrazolopyrimidine-based inhibitor with sub-micromolar affinity for activated KRAS.
- Demonstrated disruption of KRAS effector binding and inhibition of cancer cell growth.
- Elucidated key chemical interactions responsible for the inhibitor's efficacy and binding mode.
Conclusions:
- Pyrazolopyrimidine compounds show promise as a first-in-class, allosteric, noncovalent inhibitor of KRAS.
- The identified chemical features provide a roadmap for optimizing KRAS inhibitors for cancer treatment.
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