NTRK inhibitor / Sanofi - LARVOL DELTA

Discovery of BLU-847: Potent, highly selective inhibitor of the tropomysin receptor kinases TRKA, TRKB and TRKC, with in vivo activity against key clinical resistance mutations (ACS-Sp 2020) - "Treatment with approved, first-generation TRK inhibitors larotrectinib and entrectinib have led to high response rates in patients who harbor these fusion proteins...In contrast with other second generation NTRK inhibitor programs, BLU-847 was designed to specifically target wild-type TRK proteins with equipotent activity against the challenging solvent front mutations NTRK1(G595R), NTRK2(G639R), NTRK3(G623R) while maintaining exquisite kinome selectivity. We will describe the discovery of BLU-847 which utilized structure-based drug design and structure-activity relationships (SAR) to optimize overall drug properties. BLU-847 demonstrated pharmacological activity in mouse xenograft models with both wild-type and solvent-front mutations and was well-tolerated preclinically with a low projected human dose."

NTRK • NTRK1 • NTRK2 • NTRK3