An allosteric MYO9A and MYO9B inhibitor for cancer metastasis

An allosteric inhibitor of MYO9A and MYO9B, which regulate the Rho family of small guanosine triphosphatases (GTPases) that control cytoskeletal dynamics, could decrease cancer cell adhesion and migration, thereby reducing metastasis.

Functional screening a library of halogenated pseudilins and carbazole derivatives, developed to target the ATPase activity of myosins, identified 3,6-dibromo-1-(hydroxymethyl)carbazole as a top hit for its ability to inhibit the ATPase activity and motor functions of MYO9 proteins from multiple species with IC50s in the low micromolar range, while not affecting other related proteins including skeletal and cardiac myosins. Structural and biochemical analyses showed the compound, dubbed adhibin, allosterically disrupted myosin cleft movements essential for ATP turnover and force transmission. ...