5V82

PIM1 kinase in complex with Cpd17 (1-(6-(4,4-difluoropiperidin-3-yl)pyridin-2-yl)-6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine)

Summary for 5V82

• Entry DOI: 10.2210/pdb5v82/pdb
• Related: 5V80
• Descriptor: Serine/threonine-protein kinase pim-1, 1-{6-[(3R)-4,4-difluoropiperidin-3-yl]pyridin-2-yl}-6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine (3 entities in total)
• Functional Keywords: pim1, sbdd, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Isoform 2: Cytoplasm. Isoform 1: Cell membrane: P11309
• Total number of polymer chains: 1
• Total formula weight: 34854.56

Authors

Murray, J.M.,Wallweber, H. (deposition date: 2017-03-21, release date: 2017-05-10, Last modification date: 2024-03-06)

Primary citation

Wang, X.,Kolesnikov, A.,Tay, S.,Chan, G.,Chao, Q.,Do, S.,Drummond, J.,Ebens, A.J.,Liu, N.,Ly, J.,Harstad, E.,Hu, H.,Moffat, J.,Munugalavadla, V.,Murray, J.,Slaga, D.,Tsui, V.,Volgraf, M.,Wallweber, H.,Chang, J.H.
Discovery of 5-Azaindazole (GNE-955) as a Potent Pan-Pim Inhibitor with Optimized Bioavailability.
J. Med. Chem., 60:4458-4473, 2017

PubMed Abstract: 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.

PubMed: 28445037
DOI: 10.1021/acs.jmedchem.7b00418

Experimental method

X-RAY DIFFRACTION (1.888 Å)