introduction to molecules
of the month

April 2020’s molecule, the Mirati KRAS G12C inhibitor MRTX849, has been a hotly followed compound in development as it is the closest clinical KRAS inhibitor to the likely soon-to-be approved AMG-510 (sotorasib). The KRAS clinical race easily would have been the most followed development story of 2020 had it not been for COVID, due to the significant disease burden of KRAS-mutant-driven tumors in large indications including lung cancer. That Mirati’s KRAS clinical data has led to a nearly $10B appreciation in its equity value prior to an approval says everything about expectations for KRAS inhibitors in cancer. The recent successes of covalent inhibitors in cancer for targets like BTK, FGFR, and KRAS G12C are driving a major resurgence in interest for covalent inhibitors in modern drug discovery.

GS-6207 is an HIV-1 inhibitor that acts on the capsid protein monomer (p24), which normally self-assembles in the HIV virion to form the capsid core that is essential for virus infectivity. GS-6207 targets a protein-protein interaction between the small (24 kDa) p24 monomers, binding in a glue-like fashion to two separate monomers, and is able to overcome the high concentration of p24 in a virion (~4 mM!) to inhibit HIV activity with sub-nanomolar potency in cells (20-500 pM). Since the HIV capsid protein is highly conserved among HIV-1 variants, GS-6207 shows high synergy and no cross-resistance with approved anti-HIV agents. GS-6207 was found to be generally safe and well-tolerated in Ph. I and showed evidence of antiviral activity. Amazingly, this small molecule has the half-life one might expect of a well-engineered biologic drug, and is being dosed subcutaneously once every 6 months in the Ph. II/III study. Definitely a candidate for “molecule of the year!”