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Synfacts 2023; 19(11): 1147
DOI: 10.1055/s-0042-1752293
Innovative Drug Discovery and Development

Target Mutant KRAS with Molecular Glue

Contributor(s):
Dirk Trauner
,
Xiang Ji
Smith JA. M, *, Lito P. * et al. Revolution Medicines, Inc., Redwood City, Memorial Sloan Kettering Cancer Center, and Weill Cornell Medical College, New York, USA
Chemical Remodeling of a Cellular Chaperone to Target the Active State of Mutant KRAS.

Science 2023;
381: 794-799
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Key words

KRAS - molecular glue - small-molecule inhibitor - macrocyclization

Significance

KRAS is considered undruggable due to the lack of binding sites on the protein surface. The authors use a natural product-derived small molecule that binds to cellular chaperone cyclophilin A (CYPA) to form a CYPA:drug:KRASG12C tricomplex, which deactivates oncogenic signaling and leads to tumor regression in multiple human cancer models.


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Comment

The authors based their structural design on sanglifehrin A, a natural product that binds CYPA with high affinity. A SAR study conducted with various Cys-reactive warheads yields RMC-4998 as the lead compound with high potency and selectivity in inhibiting GTP-bound KRASG12C, blocking its downstream signaling activity


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Publication History

Article published online:
14 October 2023

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