Optimization of Pan-Pim Kinase Activity and Oral Bioavailability Leading to Diaminopyrazole (GDC-0339) for the Treatment of Multiple Myeloma

Pim
kinases have been targets of interest for a number of therapeutic
areas. Evidence of durable single-agent efficacy in human clinical
trials validated Pim kinase inhibition as a promising therapeutic
approach for multiple myeloma patients. Here, we report the compound
optimization leading to GDC-0339 (16), a potent, orally
bioavailable, and well tolerated pan-Pim kinase inhibitor that proved
efficacious in RPMI8226 and MM.1S human multiple myeloma xenograft
mouse models and has been evaluated as an early development candidate.