Comprehensive Report on BAY2862789 (Pasodacigib): An Investigational Diacylglycerol Kinase Alpha Inhibitor

I. Executive Summary

BAY2862789, also identified by the International Nonproprietary Name (INN) pasodacigib, is an orally bioavailable, small molecule investigational drug that selectively inhibits Diacylglycerol Kinase alpha (DGKα).[1] This agent is the product of a collaborative development effort between Bayer and the German Cancer Research Center (DKFZ).[1] Currently, BAY2862789 is undergoing Phase 1 first-in-human clinical evaluation (NCT05858164) primarily for the treatment of advanced solid tumors, with a specific focus that includes Non-Small Cell Lung Cancer (NSCLC).[1]

The mechanism of action of BAY2862789 is centered on the inhibition of DGKα, an enzyme that plays a critical regulatory role in T-cell receptor (TCR) signaling and is also implicated in cancer cell survival and proliferation.[1] By blocking DGKα, BAY2862789 prevents the phosphorylation of diacylglycerol (DAG) to phosphatidic acid (PA). This leads to an accumulation of DAG, which in turn enhances and sustains TCR-mediated signaling pathways in T-cells. The downstream consequences of this enhanced signaling include increased T-cell proliferation, restoration of T-cell effector functions, augmented cytokine production, and the activation of a more potent cytotoxic T-cell-mediated anti-tumor immune response.[3] Furthermore, because DGKα is often overexpressed in various cancer types where it contributes to cell survival and resistance to apoptosis, its inhibition by BAY2862789 may also exert direct anti-tumor effects by inducing apoptosis and suppressing the proliferation of malignant cells.[1]