molecules of the month

Context. MAP855 (Novartis Institutes for BioMedical Research) is an oral MEK1/2 active-site inhibitor. Several MEK inhibitors (e.g. cobimetinib, trametinib) have been approved for cancer, generally derived from the same allosteric pharmacophore. MEK inhibitors continue to be explored in combination with new drug mechanisms, with recent interest particularly around combinations with KRAS and RAF inhibitors. Resistance to clinical MEK combinations can involve activating mutations on MEK1/2, which the Novartis team hypothesizes results in shifting of equilibrium toward an active enzyme state. Clinical mutations tend to cluster around an autoinhibitory helix.  Mechanism of Action. An ATP-competitive, conformation-agnostic MEK inhibitor might therefore help address resistance. This is an interesting approach, as kinase drug discovery programs typically prefer to start with allosteric starting points…