Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS.
Science
; 381(6659): 794-799, 2023 08 18.
Article
em En
| MEDLINE
| ID: mdl-37590355
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. KRAS 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 KRASG12C (in which glycine-12 is mutated to cysteine). The resulting CYPAdrugKRASG12C 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 KRASG12C or multiple RAS mutants are in clinical trials now (NCT05462717 and NCT05379985).
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Produtos Biológicos
/
Proteínas Proto-Oncogênicas p21(ras)
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Chaperonas Moleculares
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Imunofilinas
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Ciclofilina A
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Neoplasias
Limite:
Humans
Idioma:
En
Revista:
Science
Ano de publicação:
2023
Tipo de documento:
Article