Indication

Target/marker/pathway

Summary

Licensing status

Publication and contact information

Cancer

Cancer

K-Ras (KRAS) G12C

In vitro studies suggest an allosteric, irreversible inhibitor of KRAS G12C could help treat cancer. A fragment-based screen yielded compounds that selectively bound oncogenic KRAS G12C and did not bind wild-type KRAS. Structure-based optimization yielded an acrylamide-based compound that irreversibly bound KRAS G12C via an allosteric site, inhibiting GTP-GDP exchange and KRAS G12C-effector protein interactions. In lung cancer cell lines expressing KRAS G12C, compared with cells expressing wild-type KRAS, the compound increased apoptosis. Next steps could include developing compounds that are active in vivo and testing them in mouse models of cancer (see Covalent hits on KRAS, page 6).

SciBX 7(1); doi:10.1038/scibx.2014.9
Published online Jan. 9, 2014

Patented; licensed to Araxes Pharma LLC

Ostrem, J.M. et al. Nature; published online Nov. 20, 2013;
doi:10.1038/nature12796
Contact: Kevan M. Shokat, University of California, San Francisco, Calif.
e-mail:

kevan.shokat@ucsf.edu