6NW2

Structure of human RIPK1 kinase domain in complex with compound 11

Summary for 6NW2

• Entry DOI: 10.2210/pdb6nw2/pdb
• Descriptor: Receptor-interacting serine/threonine-protein kinase 1, (5R)-5-methyl-N-[(3S)-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]-4,5,6,7-tetrahydro-2H-indazole-3-carboxamide (3 entities in total)
• Functional Keywords: rip1, kinase, rip, rip1k ripk1, immune system, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 71558.47

Authors

Fong, R.,Lupardus, P.J. (deposition date: 2019-02-05, release date: 2019-05-01, Last modification date: 2024-03-13)

Primary citation

Hamilton, G.L.,Chen, H.,Deshmukh, G.,Eigenbrot, C.,Fong, R.,Johnson, A.,Kohli, P.B.,Lupardus, P.J.,Liederer, B.M.,Ramaswamy, S.,Wang, H.,Wang, J.,Xu, Z.,Zhu, Y.,Vucic, D.,Patel, S.
Potent and selective inhibitors of receptor-interacting protein kinase 1 that lack an aromatic back pocket group.
Bioorg.Med.Chem.Lett., 29:1497-1501, 2019

PubMed Abstract: Receptor-interacting protein kinase 1 (RIPK1), a key component of the cellular necroptosis pathway, has gained recognition as an important therapeutic target. Pharmacologic inhibition or genetic inactivation of RIPK1 has shown promise in animal models of disease ranging from acute ischemic conditions, chronic inflammation, and neurodegeneration. We present here a class of RIPK1 inhibitors that is distinguished by a lack of a lipophilic aromatic group present in most literature inhibitors that typically occupies a hydrophobic back pocket of the protein active site. Despite not having this ubiquitous feature of many known RIPK1 inhibitors, we were able to obtain compounds with good potency, kinase selectivity, and pharmacokinetic properties in rats. The use of the lipophilic yet metabolically stable pentafluoroethyl group was critical to balancing the potency and properties of optimized analogs.

PubMed: 31000154
DOI: 10.1016/j.bmcl.2019.04.014

Experimental method

X-RAY DIFFRACTION (2 Å)