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Design, Synthesis, and T Cell Checkpoint Combination Potential Of First-In-Class DGKα/ζ Inhibitor BMS-986408.

Denise C Grünenfelder1, Upender Velaparthi2, Jayakumar S Warrier3

  • 1Bristol Myers Squibb, Research & Early Development, Cambridge, Massachusetts 02141, United States.

Journal of Medicinal Chemistry
|October 14, 2025
PubMed
Summary
This summary is machine-generated.

Diacylglycerol kinase alpha (DGKα) and zeta (DGKζ) are T cell checkpoints. Inhibiting DGKα/ζ with BMS-408 enhances T cell function and tumor immunity, showing promise for next-generation cancer immunotherapies.

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Area of Science:

  • Immunology
  • Pharmacology
  • Oncology

Background:

  • Diacylglycerol kinase alpha (DGKα) and DGKζ are intracellular checkpoints that suppress T cell signaling, activation, and anti-tumor immunity.
  • Inhibiting DGKα/ζ represents a promising strategy for next-generation cancer immunotherapy.
  • This approach has the potential to enhance responses to existing treatments like anti-PD-1 and anti-CTLA-4.

Purpose of the Study:

  • To optimize a lead molecule (BMS-502) into a first-in-class dual DGKα/ζ inhibitor for potential cancer immunotherapy.
  • To identify a development candidate with improved cellular potency, pharmacokinetic, and physicochemical properties.
  • To evaluate the preclinical efficacy and safety of the optimized inhibitor (BMS-408).

Main Methods:

  • Structure-based drug design and medicinal chemistry for molecule optimization.
  • In vitro assays to assess cellular potency and enzyme inhibition.
  • In vivo pharmacokinetic and pharmacodynamic studies in mouse models.
  • Preclinical efficacy studies using combination therapy in MC-38 and 1956 tumor models.

Main Results:

  • The development candidate BMS-408, a dual DGKα/ζ inhibitor, was identified through optimization of BMS-502.
  • BMS-408 demonstrated favorable in vitro and in vivo pharmacological profiles.
  • Preclinical studies showed dose-proportional pharmacokinetics and pharmacodynamics in mice.
  • BMS-408 exhibited robust efficacy in combination with anti-PD-1 and/or anti-CTLA-4 in relevant tumor models.

Conclusions:

  • BMS-408 is a potent, first-in-class dual DGKα/ζ inhibitor with promising preclinical anti-tumor activity.
  • The favorable in vitro and in vivo profiles support the advancement of BMS-408 into clinical development.
  • Inhibition of DGKα/ζ via BMS-408 holds potential for enhancing cancer immunotherapy.