ISM5939 is a potent and selective, orally bioavailable ENPP1 inhibitor with IC50 of 0.63 nM against the 2,3-cGAMP degradation and 9.28 nM against ATP hydrolysis.
ISM5939 is competitive with the natural substrates of ENPP1.
ISM5939 displays >3400-fold selectivity over ENPP2 and ENPP3, does not exhibit any significant agonistic or antagonistic effects against 44 clinically relevant off-targets, including GPCRs, ion channels, enzymes, nuclear receptors, and key transporters.
ISM5939 has mean IC50 of 40 nM for maintaining extracellular cGAMP levels in the presence of ENPP1-expressing cancer cells, including MDA-MB-231 breast cancer cells and H1792 lung adenocarcinoma cells.
ISM5939 stabilizes tumor-secreted cGAMP and orchestrates non-cell autonomous STING activation in antigen-presenting cells.
ISM5939 synergizes with targeting the PD-1/PD-L1 axis and chemotherapy in suppressing tumor growth with good tolerance, in murine syngeneic models across cancer types.