Design, Synthesis, and T Cell Checkpoint Combination Potential Of First-In-Class DGKα/ζ Inhibitor BMS-986408
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 <b>BMS-502</b> was optimized to the first-in-class dual DGKα/ζ inhibitor <b>BMS-986408</b> (<b>BMS-408</b>), 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 <b>BMS-408</b>. In preclinical studies, <b>BMS-408</b> 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 <i>in vitro</i> and <i>in vivo</i> profiles, as well as <i>in vivo</i> pharmacology, <b>BMS-408</b> was advanced to clinical development.
Authors
- R. M. Borzilleri
- Madhu Sudhan Ravindran (ORCID: https://orcid.org/0000-0001-7450-2001)
- Min Ding (ORCID: https://orcid.org/0000-0002-6373-7929)
- Raju Mannoori (ORCID: https://orcid.org/0009-0007-6521-6215)
- Shailesh Dudhgaonkar (ORCID: https://orcid.org/0000-0003-1694-3460)
- Michael Wichroski (ORCID: https://orcid.org/0009-0009-2664-2347)
- Robert G. Gentles
- Prasada Rao Jalagam
- Scott Martin
- Mark M. Davis (ORCID: https://orcid.org/0000-0001-6868-657X)
- Upender Velaparthi (ORCID: https://orcid.org/0000-0002-3000-9255)
- John S. Tokarski
- Prabhjyot K. Dehal (ORCID: https://orcid.org/0000-0003-1200-647X)
- Kotha Rathnakar Reddy
- Susan Wee
- Elizabeth A. Dierks (ORCID: https://orcid.org/0000-0002-3654-4064)
- Gopal Dhar
- Si-Qi Liu (ORCID: https://orcid.org/0000-0001-9727-9498)
- Mark R. Witmer (ORCID: https://orcid.org/0009-0005-6860-0920)
- Lumelle A. Schneeweis (ORCID: https://orcid.org/0000-0003-3226-0774)
- Jayakumar Warrier
- Nicholas A. Meanwell (ORCID: https://orcid.org/0000-0002-8857-1515)
- Denise C. Grünenfelder (ORCID: https://orcid.org/0000-0002-0334-2167)
- Chetan Padmakar Darne
- Swagatam Ray
- Shana Posy (ORCID: https://orcid.org/0000-0001-9298-899X)
- T. G. Murali Dhar (ORCID: https://orcid.org/0000-0003-0738-1021)
- Louis Chupak (ORCID: https://orcid.org/0009-0008-9601-9131)
- Amy A. Sarjeant (ORCID: https://orcid.org/0000-0002-1993-0406)
- Abigail E. Witt (ORCID: https://orcid.org/0009-0004-2531-2227)
- Hasibur Rahaman (ORCID: https://orcid.org/0000-0001-6981-1109)
- Dana Banas (ORCID: https://orcid.org/0000-0002-5438-1131)
- Gopikishan Tonukunuru
- Richard E. Olson (ORCID: https://orcid.org/0000-0001-5471-1404)
- Debarati M. Tagore
- Deepa Calambur
- Xiaofan Zheng
- Thiruvenkadam Raja
- Gregory Locke
- Yazhong Huang (ORCID: https://orcid.org/0000-0001-5551-2423)
- Aravind Anandam
- Ramola Sane
- Manjunatha Kamble
- Joseph G. Naglich
- Bireshwar Dasgupta
- Hua Fang (ORCID: https://orcid.org/0000-0003-1235-647X)
- Dianlin Xie
- Anoop Kumar (ORCID: https://orcid.org/0000-0001-7915-3365)
- Sagnik Chatterjee (ORCID: https://orcid.org/0000-0001-9003-1676)
- Robin Moore
- Bokka Venkata Murali
- T. Thanga Mariappan
- Hongchen Qiu
- Saumya Roy
- Erica Cook
- Emma Lees
- Sivasudar Velaiah
- R. Marcus Fancher
- Siddheshwar Layane
Institutions
- Bristol-Myers Squibb (Germany) (DE)
- Bristol-Myers Squibb (United States) (US)
- Bristol-Myers Squibb (Ireland) (IE)
- Bristol-Myers Squibb (United Kingdom) (GB)
- Bristol-Myers Squibb (Sweden) (SE)
- Bristol-Myers Squibb (Belgium) (BE)
- Bristol-Myers Squibb (India) (IN)
- Biocon (India) (IN)
- Syngene International (India) (IN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-10-14
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02240
- Citations
- 1
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 1.05