Discovery of BMS-986408, a First-In-Class Dual DGKα and DGKζ Inhibitor That Unleashes PD-1 Checkpoint and CAR T-Cell Immunotherapies

  • Cancer Immunol Res. 2025 Jun 12. doi: 10.1158/2326-6066.CIR-25-0156.
Michael Wichroski  1 ,  Si-Qi Liu  1 ,  Lauren M Zasadil  2 ,  Joseph L Benci  3 ,  Patrick C Gedeon  4 ,  Kendall J Condon  3 ,  Suhasini Joshi  5 ,  Shana Posy  3 ,  Patrick Carlson  6 ,  Alison Maier  6 ,  Jiao Shen  7 ,  Rakeeb Kureshi  8 ,  Yuka Amako  1 ,  Tai Wang  1 ,  Ryan L Powles  1 ,  Yanyun Li  1 ,  Tho Lai  3 ,  Igor Katsyv  3 ,  Hongchen Qiu  1 ,  Huilin Qi  1 ,  Jessica Wong  1 ,  Dandan Zhao  3 ,  Dana Banas  3 ,  Joelle Onorato  3 ,  Gregory Locke  9 ,  Xueer Chen  3 ,  Wen-Chi Chou  1 ,  Erica Cook  3 ,  Abigail E Witt  1 ,  Christopher M Barbieri  3 ,  Hong Zhang  1 ,  Jonathan B Olsen  3 ,  Alba Font-Tello  1 ,  Eugene Drokhlyansky  1 ,  Denise C Grünenfelder  1 ,  Louis Chupak  10 ,  Tyler A Longmire  1 ,  Jon C Jones  3 ,  Travis J Hollmann  11 ,  David G Kugler  6 ,  John N Feder  3 ,  Raphael Bueno  12 ,  John Wain  4 ,  Pallavur Sivakumar  9 ,  Yu Liu  1 ,  Stephanie K Dougan  8 ,  Cloud P Paweletz  13 ,  David A Barbie  8 ,  Emma Lees  14
Affiliations
  • 1. Bristol-Myers Squibb (United States), Cambridge, MA, United States.
  • 2. Dana-Farber Cancer Institute, Boston, MASSACHUSETTS, United States.
  • 3. Bristol-Myers Squibb (United States), Lawrenceville, NJ, United States.
  • 4. Brigham and Women's Hospital, Boston, MA, United States.
  • 5. Bristol-Myers Squibb (United States), Brisbane, CA, United States.
  • 6. Bristol-Myers Squibb (United States), Seattle, WA, United States.
  • 7. Dana-Farber Cancer Institute, Boston, United States.
  • 8. Dana-Farber Cancer Institute, Boston, MA, United States.
  • 9. Bristol-Myers Squibb (United States), United States.
  • 10. Dunad Therapeutics, Boston, MA, United States.
  • 11. Bristol-Myers Squibb (United States), Lawrence Twp, NJ, United States.
  • 12. Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.
  • 13. Dana-Farber Cancer Institute, Boston, Massachusetts, United States.
  • 14. Bristol-Myers Squibb (United States), Cambridge, CA, United States.
PMID: 40506249 DOI: 10.1158/2326-6066.CIR-25-0156
Abstract

Diacylglycerol kinase α (DGKα) and DGKζ are lipid kinases that negatively regulate T-cell signaling through diacylglycerol (DAG) metabolism, making them attractive targets for next-generation immunotherapy. Here, we report the discovery and pre-clinical characterization of the clinical-stage DGKα and DGKζ lipid kinase inhibitor, BMS-986408. BMS-986408 binds to the accessory subdomain of the catalytic domain and inhibits DGKα/ζ through a mechanism of action that includes competitive inhibition for the DAG substrate, subcellular translocation to the plasma membrane, and proteosome-dependent degradation. DGKα/ζ inhibition markedly improved the therapeutic benefit of PD-1 therapy by unleashing T-cell responses in the tumor while also amplifying the priming and expansion of tumor-reactive T cells in the tumor-draining lymph nodes. Simultaneous inhibition of both DGKα and DGKζ was required to maximize combination benefit with PD-1 therapy. Further, we observed in non-small cell lung Cancer (NSCLC) patient samples that DGKα and DGKζ were broadly expressed in tumor-infiltrated T cells and combination therapy invigorated a robust cytokine response in NSCLC patient-derived organotypic tumors supporting the clinical evaluation of this combination in NSCLC patients. BMS-986408 also markedly improved CD19-targeted CAR T-cell therapy efficacy by overcoming hypo-functionality, insufficient expansion, and lack of co-stimulatory ligands. BMS-986408 represents a critical step toward evaluating the broad immunotherapy potential of DGKα/ζ inhibitors in Cancer patients.

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