6RLN

Crystal structure of RIP1 kinase in complex with GSK3145095

Summary for 6RLN

• Entry DOI: 10.2210/pdb6rln/pdb
• Descriptor: Receptor-interacting serine/threonine-protein kinase 1, ~{N}-[(3~{S})-7,9-bis(fluoranyl)-2-oxidanylidene-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-3-(phenylmethyl)-1~{H}-1,2,4-triazole-5-carboxamide (3 entities in total)
• Functional Keywords: inhibitor, complex, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 69988.54

Authors

Thorpe, J.H.,Harris, P.A. (deposition date: 2019-05-02, release date: 2019-07-03, Last modification date: 2024-01-24)

Primary citation

Harris, P.A.,Marinis, J.M.,Lich, J.D.,Berger, S.B.,Chirala, A.,Cox, J.A.,Eidam, P.M.,Finger, J.N.,Gough, P.J.,Jeong, J.U.,Kang, J.,Kasparcova, V.,Leister, L.K.,Mahajan, M.K.,Miller, G.,Nagilla, R.,Ouellette, M.T.,Reilly, M.A.,Rendina, A.R.,Rivera, E.J.,Sun, H.H.,Thorpe, J.H.,Totoritis, R.D.,Wang, W.,Wu, D.,Zhang, D.,Bertin, J.,Marquis, R.W.
Identification of a RIP1 Kinase Inhibitor Clinical Candidate (GSK3145095) for the Treatment of Pancreatic Cancer.
Acs Med.Chem.Lett., 10:857-862, 2019

PubMed Abstract: RIP1 regulates cell death and inflammation and is believed to play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases and cancer. While small-molecule inhibitors of RIP1 kinase have been advanced to the clinic for inflammatory diseases and CNS indications, RIP1 inhibitors for oncology indications have yet to be described. Herein we report on the discovery and profile of GSK3145095 (compound ). Compound potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking RIP1 kinase-dependent cellular responses. Highlighting its potential as a novel cancer therapy, the inhibitor was also able to promote a tumor suppressive T cell phenotype in pancreatic adenocarcinoma organ cultures. Compound is currently in phase 1 clinical studies for pancreatic adenocarcinoma and other selected solid tumors.

PubMed: 31223438
DOI: 10.1021/acsmedchemlett.9b00108

Experimental method

X-RAY DIFFRACTION (2.87 Å)