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.

中文翻译：

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发现5-氮杂吲唑（GNE-955）作为具有最佳生物利用度的有效泛肽抑制剂

Pim激酶已被确定为血液肿瘤学适应症（包括多发性骨髓瘤和某些白血病）的有希望的治疗靶标。在这里，我们描述了我们在通过提高生物利用度同时优化对所有三种Pim激酶同工型的抑制力的同时优化铅系列的努力。广泛的肠道代谢和主要代谢产物的发现有助于完善我们的设计策略，并且我们观察到，首先优化药代动力学特性，然后优化功效是比反向方法更成功的方法。在最终的工作中，发现了类似的类似物，例如20（GNE-955），其带有5-氮杂吲唑核，其铰链具有非规范的氢键。