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

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

  • ACS Med Chem Lett. 2019 May 9;10(6):857-862. doi: 10.1021/acsmedchemlett.9b00108.
Philip A Harris 1,  Jill M Marinis 1,  John D Lich 1,  Scott B Berger 1,  Anirudh Chirala 2,  Julie A Cox 1,  Patrick M Eidam 1,  Joshua N Finger 1,  Peter J Gough 1,  Jae U Jeong 1,  James Kang 1,  Viera Kasparcova 1,  Lara K Leister 1,  Mukesh K Mahajan 1,  George Miller 2 2,  Rakesh Nagilla 1,  Michael T Ouellette 1,  Michael A Reilly 1,  Alan R Rendina 1,  Elizabeth J Rivera 1,  Helen H Sun 1,  James H Thorpe 3,  Rachel D Totoritis 1,  Wei Wang 2,  Dongling Wu 2,  Daohua Zhang 1,  John Bertin 1,  Robert W Marquis 1
Affiliations

Affiliations

  • 1 Pattern Recognition Receptor DPU and Medicinal Science & Technology, GlaxoSmithKline, Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  • 2 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.
  • 3 Medicinal Science & Technology, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
PMID: 31223438 DOI: 10.1021/acsmedchemlett.9b00108
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 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.

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