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Discovery of 5-Azaindazole (GNE-955) as a Potent Pan-Pim Inhibitor with Optimized Bioavailability.

Xiaojing WangAleksandr KolesnikovSuzanne TayGrace ChanQi ChaoSteven DoJason DrummondAllen J EbensNing LiuJustin LyEric HarstadHuiyong HuJohn MoffatVeerendra MunugalavadlaJeremy MurrayDionysos SlagaVickie TsuiMatthew VolgrafHeidi WallweberJae H Chang
Published in: Journal of medicinal chemistry (2017)
Pim kinases have been identified as promising therapeutic targets for hematologic-oncology indications, including multiple myeloma and certain leukemia. Here, we describe our continued efforts in optimizing a lead series by improving bioavailability while maintaining high inhibitory potency against all three Pim kinase isoforms. The discovery of extensive intestinal metabolism and major metabolites helped refine our design strategy, and we observed that optimizing the pharmacokinetic properties first and potency second was a more successful approach than the reverse. In the resulting work, novel analogs such as 20 (GNE-955) were discovered bearing 5-azaindazole core with noncanonical hydrogen bonding to the hinge.
Keyphrases
  • small molecule
  • multiple myeloma
  • high throughput
  • acute myeloid leukemia
  • palliative care
  • ms ms
  • bone marrow
  • tyrosine kinase
  • single cell