molecules of the month

MRTX1133 was nominated as December 2021’s cover molecule by reviewers Joachim Rudolph and Julien Lefranc. MRTX1133 is a non-covalent inhibitor of KRASG12D that demonstrated tumor regression in a mouse xenograft model when dosed IP (maximum efficacy at 10-30 mg/kg, activity as low as 3 mg/kg). Joachim said, “The discovery of MRTX1133 deserves major credit as the first reported potent and selective non-covalent mutant-specific KRAS inhibitor especially as the targeted G12D mutant is the most prevalent KRAS mutant (33% among KRAS mutant tumors). The paper represents a successful continuation of the work on KRAS G12C inhibitors demonstrating suitability of the same binding site (switch II pocket) for mutants outside of G12C.” “This reflects, in retrospect, the power of covalent screening as…