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 U Jeong; James Kang; Viera Kasparcova; Lara K Leister; Mukesh K. Mahajan; George Miller; Rakesh Nagilla; Michael T. Ouellette; Michael A. 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
ACS Med. Chem. Lett., 2019, 10, 6, 857-862
https://doi.org/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 hu-man 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 oncol-ogy 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 pro-mote 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.