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

2019; American Chemical Society; Volume: 10; Issue: 6 Linguagem: Inglês

10.1021/acsmedchemlett.9b00108

1948-5875

Philip A. Harris, Jill M. Marinis, John D. Lich, Scott B. Berger, Anirudh Chirala, Julie A. Cox, Patrick M. Eidam, Joshua N. Finger, Peter J. Gough, Jae Uk Jeong, James Kang, Viera Kasparcova, Lara K. Leister, Mukesh Mahajan, George Miller, Rakesh Nagilla, Michael T. Ouellette, Michael Reilly, Alan R. Rendina, Elizabeth J. Rivera, Helen H. Sun, James H. Thorpe, Rachel D. Totoritis, Wei Wang, Dongling Wu, Daohua Zhang, John Bertin, Robert W. Marquis,

interferon and immune responses

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.