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Updated: Jul 31, 2026
Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
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.
Abstract:
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.
Insights
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.
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.
