TXN10128: An Oral ENPP1 Inhibitor Enhancing STING Activation and Synergy with Immune Checkpoint Blockade for Anti-Tumor Activity

The study focuses on the development of an orally administered small molecule that can stimulate the innate immune system and potentially convert 'cold' tumors into 'hot' ones, enhancing their response to immunotherapies. The compound, TXN10128, is an ENPP1 inhibitor, which prevents the breakdown of 2'3'-cGAMP, a molecule that activates the STING pathway, thus promoting an immune response against cancer cells. The research involved enzymatic and cellular assays to measure the inhibitory activity of TXN10128 on ENPP1 and its subsequent effect on STING activation. Additionally, the compound's impact on innate immune responses was evaluated through assays that assess lymphocyte infiltration and tumor growth in a 3D co-culture model.

TXN10128 demonstrated potent inhibition of ENPP1 in enzymatic assays and induced STING activation in cellular assays. It also enhanced lymphocyte infiltration and inhibited tumor spheroid growth in the 3D co-culture condition. The compound showed favorable drug-like properties for oral administration and its systemic exposure through oral dosing synergized with an anti-PD-L1 antibody to inhibit tumor growth and improve the profile of tumor-infiltrating lymphocytes in the MC38 syngeneic model. Ongoing in vivo studies aim to broaden the range of cancer types that can be treated with TXN10128.

The conclusion of the study is that TXN10128 is a potent and selective ENPP1 inhibitor that can stimulate an immune response in a 3D co-culture setting, which correlates with tumor growth inhibition and an improved lymphocyte profile in animal models. With its promising drug-like characteristics, the research indicates that TXN10128 is a viable candidate for further clinical investigation as a complement to current immunotherapies.