Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS.
basic_science · Level V
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- Record sourced from PubMed, PMID 37590355.
- Also identified by DOI 10.1126/science.adg9652 and PMC identifier 10474815.
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Abstract
The discovery of small-molecule inhibitors requires suitable binding pockets on protein surfaces. Proteins that lack this feature are considered undruggable and require innovative strategies for therapeutic targeting. <i>KRAS</i> is the most frequently activated oncogene in cancer, and the active state of mutant KRAS is such a recalcitrant target. We designed a natural product-inspired small molecule that remodels the surface of cyclophilin A (CYPA) to create a neomorphic interface with high affinity and selectivity for the active state of KRAS<sup>G12C</sup> (in which glycine-12 is mutated to cysteine). The resulting CYPA:drug:KRAS<sup>G12C</sup> tricomplex inactivated oncogenic signaling and led to tumor regressions in multiple human cancer models. This inhibitory strategy can be used to target additional KRAS mutants and other undruggable cancer drivers. Tricomplex inhibitors that selectively target active KRAS<sup>G12C</sup> or multiple RAS mutants are in clinical trials now (NCT05462717 and NCT05379985).
Medical subject headings
- Biological Products
- Molecular Chaperones
- Proto-Oncogene Proteins p21(ras)
- Cyclophilin A
- Immunophilins
- Neoplasms