BMS-502 / BMS - LARVOL DELTA

Endogenous tracking reveals paralog-specific targets for phosphatidic acid generation during phospholipase C signaling in living cells. (PubMed, J Biol Chem) - "Live-cell imaging experiments using BMS-502 with carbachol stimulation of endogenous muscarinic receptors showed that inhibition of both DGKα and the PLDs is needed to substantially reduce PA levels during PLC activation. Our findings both identify paralog-specific druggable targets for modulating PLC signaling events, and establish a new platform for characterizing DGK and PLD activity in living cells."

Journal

In Cellulo pharmacological profiling and genomic editing reveals paralog-specific targets for PA generation during PLC signaling. (PubMed, bioRxiv) - "Live-cell imaging experiments using BMS-502 with carbachol stimulation of endogenous muscarinic receptors showed that inhibition of both DGKalpha and the PLDs is needed to substantially reduce PA levels during PLC activation. Our findings both identify paralog-specific druggable targets for modulating PLC signaling events, and establish a new platform that translates typical biochemical dose response assays in cellulo."

Journal

Design, Synthesis, and T Cell Checkpoint Combination Potential Of First-In-Class DGKα/ζ Inhibitor BMS-986408. (PubMed, J Med Chem) - "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. 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."

Journal • Oncology

In Silico Identification and Characterization of Spiro[1,2,4]triazolo[1,5-c]quinazolines as Diacylglycerol Kinase α Modulators. (PubMed, Molecules) - "Through structure-based computational design using the CB-Dock2 platform with human DGK-α (PDB ID: 6IIE), 40 novel compounds were systematically evaluated along with established inhibitors (ritanserin, R59022, R59949, BMS502, and (5Z,2E)-CU-3) across five distinct binding pockets...Detailed molecular interaction mapping identified critical binding determinants, including strategic hydrogen bonding with TRP151, GLU166, and ARG126. The multidimensional evaluation identified compounds 13, 18, 33, and 40 as particularly promising candidates that balance potent target engagement with favorable pharmaceutical profiles, establishing this scaffold as a valuable platform for developing next-generation therapeutics targeting DGK-α -mediated signaling pathways."

Journal • CNS Disorders • Oncology