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    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.


    Xiaojing Wang, Aleksandr Kolesnikov, Suzanne Tay, Grace Chan, Qi Chao, Steven Do, Jason Drummond, Allen J Ebens, Ning Liu, Justin Ly, Eric Harstad, Huiyong Hu, John Moffat, Veerendra Munugalavadla, Jeremy Murray, Dionysos Slaga, Vickie Tsui, Matthew Volgraf, Heidi Wallweber, Jae H Chang. Discovery of 5-Azaindazole (GNE-955) as a Potent Pan-Pim Inhibitor with Optimized Bioavailability. Journal of medicinal chemistry. 2017 May 25;60(10):4458-4473

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    PMID: 28445037

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