Optimization of Pan-Pim Kinase Activity and Oral Bioavailability Leading to Diaminopyrazole (GDC-0339) for the Treatment of Multiple Myeloma.
Xiaojing WangWesley BlackabyVivienne AllenGrace Ka Yan ChanJae H ChangPo-Chang ChiangCoura DièneJason DrummondSteven DoEric FanEric B HarstadAlastair HodgesHuiyong HuWei JiaWilliam KofieAleksandr KolesnikovJoseph P LyssikatosJustin LyMizio MatteucciJohn G MoffatVeerendra MunugalavadlaJeremy M MurrayDavid NashCameron L NolandGeoff Del RosarioLeanne RossCraig RouseAndrew SharpeDionysos SlagaMinghua SunVickie TsuiHeidi WallweberShang-Fan YuAllen J EbensPublished in: Journal of medicinal chemistry (2019)
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.