Article
作者: Kumar, Anoop ; Olson, Richard E. ; Roy, Saumya ; Qiu, Hongchen ; Wichroski, Michael ; Dierks, Elizabeth ; Kamble, Manjunatha Narayana Rao ; Reddy, Kotha Rathnakar ; Moore, Robin ; Jalagam, Prasada R. ; Cook, Erica ; Xie, Dianlin ; Banas, Dana ; Fancher, R. Marcus ; Anandam, Aravind ; Rahaman, Hasibur ; Chupak, Louis ; Sarjeant, Amy ; Ding, Min ; Posy, Shana L. ; Zheng, Xiaofan ; Borzilleri, Robert ; Dhar, Gopal ; Tagore, Debarati M. ; Dhar, T. G. Murali ; Fang, Hua ; Meanwell, Nicholas A. ; Velaparthi, Upender ; Dudhgaonkar, Shailesh ; Dehal, Priya ; Dasgupta, Bireshwar ; Locke, Gregory ; Grünenfelder, Denise C. ; Witt, Abigail E. ; Sane, Ramola ; Naglich, Joseph G. ; Gentles, Robert ; Witmer, Mark ; Liu, Si-Qi ; Warrier, Jayakumar S. ; Mariappan, Thanga ; Velaiah, Sivasudar ; Calambur, Deepa ; Ray, Swagatam ; Darne, Chetan Padmakar ; Huang, Yazhong ; Davis, Myrtle ; Raja, Thiruvenkadam ; Lees, Emma ; Tonukunuru, Gopikishan ; Ravindran, Madhu Sudhan ; Murali, Bokka Venkata ; Chatterjee, Sagnik ; Schneeweis, Lumelle ; Mannoori, Raju ; Tokarski, John S. ; Wee, Susan ; Layane, Siddheshwar ; Martin, Scott
DGKα and DGKζ are intracellular T cell checkpoints that negatively regulate T cell signaling, activation, and tumor immunity. Inhibition of DGKα/ζ is an attractive mechanism for next-generation immunotherapy, with the potential to broaden the response to existing cancer treatments, including anti-PD-1 and anti-CTLA-4. The lead molecule BMS-502 was optimized to the first-in-class dual DGKα/ζ inhibitor BMS-986408 (BMS-408), starting with the replacement of an aryl nitro group that posed a potential liability. Subsequent improvement in cellular potency, cross-species oral pharmacokinetic profile, and optimization of physicochemical properties led to the identification of the development candidate BMS-408. In preclinical studies, BMS-408 demonstrated dose-proportional pharmacokinetics and pharmacodynamics in mice, as well as robust efficacy in combination with either anti-PD-1 and/or anti-CTLA-4 in MC-38 and 1956 tumor models. Given the favorable in vitro and in vivo profiles, as well as in vivo pharmacology, BMS-408 was advanced to clinical development.