ADT-030 is a potent, selective Phosphodiesterase 10 (PDE10) inhibitor, inhibits enzymatic activity of recombinant PDE10 using cAMP and cGMP as substrates with IC50 of 0.95 uM and 1.15 uM respectively.
ADT-030 inhibits the proliferation of a series of KRAS G12D and KRAS G12C mutant PDAC cell lines with IC50 values in the low micromolar range (1.8-4.5 uM).
ADT-030 selectively inhibits the proliferation of KRAS mutant PDAC cells, but not KRAS wild-type PDAC cell line BxPC-3.
ADT-030 inhibits the proliferation, colony formation, and motility of PDAC cell lines harboring KRASG12D and KRASG12C mutations.
ADT-030 induces apoptosis and G2/M cell cycle arrest in PDAC cells.
ADT-030 blocks PDE10 and activates PKA/PKG to reduce β-catenin levels and inhibit RAS signaling.
ADT-030 also inhibits the growth of KRASG12D and KRASG12C mutant PDAC cells resistant to allele-specific KRAS inhibitors.
ADT-030 significantly suppressed tumor growth, reduced lung and liver metastasis, and increased survival without systemic toxicity in syngeneic and patient-derived xenograft (PDX) PDAC models.