5V80

PIM1 kinase in complex with Cpd1 (1-methyl-4-(3-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)piperazin-2-one)

5V80 の概要

• エントリーDOI: 10.2210/pdb5v80/pdb
• 分子名称: Serine/threonine-protein kinase pim-1, PHOSPHATE ION, 1-methyl-4-{3-[6-(piperazin-1-yl)pyridin-2-yl]-1H-pyrazolo[3,4-c]pyridin-5-yl}piperazin-2-one, ... (4 entities in total)
• 機能のキーワード: pim1, sbdd, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Isoform 2: Cytoplasm. Isoform 1: Cell membrane: P11309
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34934.57

構造登録者

Murray, J.M.,Wallweber, H. (登録日: 2017-03-21, 公開日: 2018-04-18, 最終更新日: 2024-03-06)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.252 Å)