ISM5939 + cisplatin

ISM5939 + cisplatin is an experimental **combination therapy** of ISM5939, an orally bioavailable small-molecule ENPP1 inhibitor, and cisplatin, a DNA-damaging platinum chemotherapy agent. **ISM5939**, designed using AI by Insilico Medicine, selectively blocks ENPP1, which is a key regulator of cGAMP degradation, thereby enhancing activation of the **cGAS-STING pathway** in tumors and boosting antitumor immunity. Mechanistically, this leads to increased activation of antigen-presenting cells and CD8+ T cell responses in the tumor microenvironment, facilitating greater efficacy of immune-mediated tumor killing and synergizing with DNA-damaging agents such as cisplatin. Cisplatin, an approved chemotherapeutic, crosslinks DNA to promote cancer cell death, and when combined with ISM5939, the regimen has demonstrated greater tumor inhibition and immune activation in preclinical solid tumor models, including breast and lung cancers, than either agent alone. ISM5939 alone or combined with chemotherapy was shown in preclinical models to enhance innate and adaptive immune activity within tumors, characterized by upregulation of interferon responses, increased infiltration of CD8+ T cells and M1 macrophages, and downregulation of immunosuppressive cell types. The doublet is under development for treatment-refractory or hard-to-treat solid tumors.