5DGZ

Discovery of 3,5-substituted 6-azaindazoles as potent pan-Pim inhibitors

Summary for 5DGZ

• Entry DOI: 10.2210/pdb5dgz/pdb
• Related: 5DHJ 5DIA
• Descriptor: Serine/threonine-protein kinase pim-1, (2S)-1-(1H-INDOL-3-YL)-3-{[5-(3-METHYL-1H-INDAZOL-5-YL)PYRIDIN-3-YL]OXY}PROPAN-2-AMINE, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: pim-1, kinase, atp-competitive, structure-based drug design, transferase-transferase inhibitor complex, transferase/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: 35034.56

Authors

Murray, J.M.,Wallweber, H.,Steffek, M. (deposition date: 2015-08-29, release date: 2015-10-28, Last modification date: 2024-03-06)

Primary citation

Hu, H.,Wang, X.,Chan, G.K.,Chang, J.H.,Do, S.,Drummond, J.,Ebens, A.,Lee, W.,Ly, J.,Lyssikatos, J.P.,Murray, J.,Moffat, J.G.,Chao, Q.,Tsui, V.,Wallweber, H.,Kolesnikov, A.
Discovery of 3,5-substituted 6-azaindazoles as potent pan-Pim inhibitors.
Bioorg.Med.Chem.Lett., 25:5258-5264, 2015

PubMed Abstract: Pim kinase inhibitors are promising cancer therapeutics. Pim-2, among the three Pim isoforms, plays a critical role in multiple myeloma yet inhibition of Pim-2 is challenging due to its high affinity for ATP. A co-crystal structure of a screening hit 1 bound to Pim-1 kinase revealed the key binding interactions of its indazole core within the ATP binding site. Screening of analogous core fragments afforded 1H-pyrazolo[3,4-c]pyridine (6-azaindazole) as a core for the development of pan-Pim inhibitors. Fragment and structure based drug design led to identification of the series with picomolar biochemical potency against all three Pim isoforms. Desirable cellular potency was also achieved.

PubMed: 26459208
DOI: 10.1016/j.bmcl.2015.09.052

Experimental method

X-RAY DIFFRACTION (2.502 Å)