Publication in European Journal of Medicinal Chemistry on covalent fragment mapping of KRasG12C which reveals novel chemotypes with in vivo potency
As a member of KRAS Consortium, KINETO Lab was big part of the research to identify fragments as suitable starting points targeting KRasG12C, pre-selected in covalent fragment screening of the electrophilic fragment library. Two hits, CFL-120 and CFL-137, confirming their cellular activity against a number of homozygous and heterozygous KRasG12C tumor cells, in comparison to wild type Kras cancerous and non-cancerous cells, were finally tested in vivo using a mouse xenograft model of human lung carcinoma. The fragments demonstrated comparable in vivo efficacy to ARS-1620, the optimized KRasG12C inhibitor which served as a prototype for those molecules that reached the clinic. Our results suggest that CFL-120 and CFL-137 being new specific KRasG12C inhibitor chemotypes demonstrating promising cellular and in vivo efficacy that nominates them for further optimization.
The publication can be accessed under the following link.