Fig. 4
From: The path to the clinic: a comprehensive review on direct KRASG12C inhibitors
This figure illustrates the chemical structures of the first direct KRASG12C 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 KRASG12C 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