Fig. 4.

This figure illustrates the chemical structures of the first direct KRAS^G12C inhibitors in the preclinical and clinical years. Compound 12 was the initial lead compound developed by the Shokat lab; it was subsequently optimized to ARS-853, the first direct small molecular inhibitor shown to selectively inhibit KRAS^G12C in cells with potency in the range of a drug candidate. Introduction of a quinazoline core and a fluorophenol hydrophobic binding moiety resulted in ARS-1620, the first drug candidate to demonstrate in vivo potency. In May 2021, AMG510 (sotorasib) became the first FDA-approved therapy to directly target KRAS-mutated tumors. In June 2021, MRTX849 (adagrasib) received breakthrough therapy designation by the FDA, driving MRTX849 nearer to entering the clinic as well