Allosteric inhibitor of PGAM1 identified for NSCLC
INDICATION: Non-small cell lung cancer (NSCLC)
A benzenesulfonamide-based allosteric inhibitor of PGAM1, given alone or in combination with the EGFR inhibitor Tarceva erlotinib, could treat NSCLC. Structure-based optimization of a previously reported PGAM1 inhibitor yielded a benzenesulfonamide that non-competitively inhibited the target in vitro with an IC50 of 0.85 μM, and inhibited growth of four human NSCLC cell lines with IC50 values of 0.79-5.62 μM -- improvements of seven to 23-fold over the previously reported compound. Docking studies confirmed the compound bound PGAM1 at an allosteric site. The PGAM1 inhibitor sensitized two Tarceva-resistant xenograft mouse models of NSCLC to Tarceva, and in mice with metastatic NSCLC, the PGAM1 inhibitor alone reduced the number of metastatic lesions...