Development of a Manufacturing Route toward AMG 193, an MTA-Cooperative PRMT5 Inhibitor

AMG 193 is an MTA-cooperative PRMT5 inhibitor that has shown promising antitumor activity in the clinic. Despite a five-month development window from molecule identification to multi-kg manufacture of this small molecule drug substance, a robust process was developed, featuring multiple bio- and chemocatalytic steps. In particular, two wild-type enzymes were applied to the synthesis of key building blocks, including the formation of a chiral morpholine fragment, which was further improved through directed evolution. Additionally, a selective Ir-catalyzed C–H borylation, followed by a Pd-catalyzed Suzuki coupling and cyclization, was executed in a single pot, enabling rapid access to the naphthyridine core. Altogether, the development of this convergent synthesis has enabled a continued supply of AMG 193 for clinical studies.