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

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.