6OKO

Crystal structure of mRIPK3 complexed with N-(3-fluoro-4-{1H-pyrrolo[2,3-b]pyridin-4-yloxy}phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Summary for 6OKO

• Entry DOI: 10.2210/pdb6oko/pdb
• Descriptor: Receptor-interacting serine/threonine-protein kinase 3, 1-(4-fluorophenyl)-N-[3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide (3 entities in total)
• Functional Keywords: kinase, ripk3, rip3, transferase
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 2
• Total formula weight: 73343.49

Authors

Pokross, M.E. (deposition date: 2019-04-14, release date: 2019-07-17, Last modification date: 2024-03-13)

Primary citation

Hart, A.C.,Abell, L.,Guo, J.,Mertzman, M.E.,Padmanabha, R.,Macor, J.E.,Chaudhry, C.,Lu, H.,O'Malley, K.,Shaw, P.J.,Weigelt, C.,Pokross, M.,Kish, K.,Kim, K.S.,Cornelius, L.,Douglas, A.E.,Calambur, D.,Zhang, P.,Carpenter, B.,Pitts, W.J.
Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage.
Acs Med.Chem.Lett., 11:266-271, 2020

PubMed Abstract: Necroptosis has been implicated in a variety of disease states, and RIPK3 is one of the kinases identified to play a critical role in this signaling pathway. In an effort to identify RIPK3 kinase inhibitors with a novel profile, mechanistic studies were incorporated at the hit triage stage. Utilization of these assays enabled identification of a Type II DFG-out inhibitor for RIPK3, which was confirmed by protein crystallography. Structure-based drug design on the inhibitors targeting this previously unreported conformation enabled an enhancement in selectivity against key off-target kinases.

PubMed: 32184955
DOI: 10.1021/acsmedchemlett.9b00065

Experimental method

X-RAY DIFFRACTION (2.1 Å)