Identification of a RIP1 Kinase Inhibitor Clinical Candidate (GSK3145095) for the Treatment of Pancreatic Cancer.

Autor:	Harris PA; Pattern Recognition Receptor DPU and Medicinal Science & Technology, GlaxoSmithKline, Collegeville Road, Collegeville, Pennsylvania 19426, United States., Marinis JM; Pattern Recognition Receptor DPU and Medicinal Science & Technology, GlaxoSmithKline, Collegeville Road, Collegeville, Pennsylvania 19426, United States., Lich JD; Pattern Recognition Receptor DPU and Medicinal Science & Technology, GlaxoSmithKline, Collegeville Road, Collegeville, Pennsylvania 19426, United States., Berger SB; Pattern Recognition Receptor DPU and Medicinal Science & Technology, GlaxoSmithKline, Collegeville Road, Collegeville, Pennsylvania 19426, United States., Chirala A; S. Arthur Localio Laboratory and Department of Cell Biology, New York University School of Medicine, 550 First Avenue, New York, New York 10016, United States., Cox JA; Pattern Recognition Receptor DPU and Medicinal Science & Technology, GlaxoSmithKline, Collegeville Road, Collegeville, Pennsylvania 19426, United States., Eidam PM; Pattern Recognition Receptor DPU and Medicinal Science & Technology, GlaxoSmithKline, Collegeville Road, Collegeville, Pennsylvania 19426, United States., Finger JN; Pattern Recognition Receptor DPU and Medicinal Science & Technology, GlaxoSmithKline, Collegeville Road, Collegeville, Pennsylvania 19426, United States., Gough PJ; Pattern Recognition Receptor DPU and Medicinal Science & Technology, GlaxoSmithKline, Collegeville Road, Collegeville, Pennsylvania 19426, United States., Jeong JU; Pattern Recognition Receptor DPU and Medicinal Science & Technology, GlaxoSmithKline, Collegeville Road, Collegeville, Pennsylvania 19426, United States., Kang J; Pattern Recognition Receptor DPU and Medicinal Science & Technology, GlaxoSmithKline, Collegeville Road, Collegeville, Pennsylvania 19426, United States., Kasparcova V; Pattern Recognition Receptor DPU and Medicinal Science & Technology, GlaxoSmithKline, Collegeville Road, Collegeville, Pennsylvania 19426, United States., Leister LK; Pattern Recognition Receptor DPU and Medicinal Science & Technology, GlaxoSmithKline, Collegeville Road, Collegeville, Pennsylvania 19426, United States., Mahajan MK; Pattern Recognition Receptor DPU and Medicinal Science & Technology, GlaxoSmithKline, Collegeville Road, Collegeville, Pennsylvania 19426, United States., Miller G; S. Arthur Localio Laboratory and Department of Cell Biology, New York University School of Medicine, 550 First Avenue, New York, New York 10016, United States.; S. Arthur Localio Laboratory and Department of Cell Biology, New York University School of Medicine, 550 First Avenue, New York, New York 10016, United States., Nagilla R; Pattern Recognition Receptor DPU and Medicinal Science & Technology, GlaxoSmithKline, Collegeville Road, Collegeville, Pennsylvania 19426, United States., Ouellette MT; Pattern Recognition Receptor DPU and Medicinal Science & Technology, GlaxoSmithKline, Collegeville Road, Collegeville, Pennsylvania 19426, United States., Reilly MA; Pattern Recognition Receptor DPU and Medicinal Science & Technology, GlaxoSmithKline, Collegeville Road, Collegeville, Pennsylvania 19426, United States., Rendina AR; Pattern Recognition Receptor DPU and Medicinal Science & Technology, GlaxoSmithKline, Collegeville Road, Collegeville, Pennsylvania 19426, United States., Rivera EJ; Pattern Recognition Receptor DPU and Medicinal Science & Technology, GlaxoSmithKline, Collegeville Road, Collegeville, Pennsylvania 19426, United States., Sun HH; Pattern Recognition Receptor DPU and Medicinal Science & Technology, GlaxoSmithKline, Collegeville Road, Collegeville, Pennsylvania 19426, United States., Thorpe JH; Medicinal Science & Technology, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K., Totoritis RD; Pattern Recognition Receptor DPU and Medicinal Science & Technology, GlaxoSmithKline, Collegeville Road, Collegeville, Pennsylvania 19426, United States., Wang W; S. Arthur Localio Laboratory and Department of Cell Biology, New York University School of Medicine, 550 First Avenue, New York, New York 10016, United States., Wu D; S. Arthur Localio Laboratory and Department of Cell Biology, New York University School of Medicine, 550 First Avenue, New York, New York 10016, United States., Zhang D; Pattern Recognition Receptor DPU and Medicinal Science & Technology, GlaxoSmithKline, Collegeville Road, Collegeville, Pennsylvania 19426, United States., Bertin J; Pattern Recognition Receptor DPU and Medicinal Science & Technology, GlaxoSmithKline, Collegeville Road, Collegeville, Pennsylvania 19426, United States., Marquis RW; Pattern Recognition Receptor DPU and Medicinal Science & Technology, GlaxoSmithKline, Collegeville Road, Collegeville, Pennsylvania 19426, United States.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2019 May 09; Vol. 10 (6), pp. 857-862. Date of Electronic Publication: 2019 May 09 (Print Publication: 2019).
DOI:	10.1021/acsmedchemlett.9b00108
Abstrakt:	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 6 ). Compound 6 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 6 is currently in phase 1 clinical studies for pancreatic adenocarcinoma and other selected solid tumors. Competing Interests: The authors declare the following competing financial interest(s): All authors, with the exception of George Miller, Wei Wang, Anirudh Chirala, and Dongling Wu, are current employees and stockholders of GlaxoSmithKline.
Databáze:	MEDLINE
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