ART0380 (ART-0380) is a potent, selective and ATP-competitive ATR kinase inhibitor, inhibits ATR-ATRIP complex enzyme activity with IC50 of 51.7 nM, and phospho-Chk1 IC50 of 22 nM in cell western assay.
ART0380 shows no effect on downstream markers of the ATR related enzymes ATM, DNA-PKcs, mTOR, and SMG1 at 3 uM in response to DNA damage induced by etoposide in NCI-H460 cells.
ART0380 induces robust inhibition of cell growth (LoVo, EC50=1 uM; NCI-H23, EC50=0.13 uM), with little to no effect in CCD-18Co normal fibroblasts (EC50=6.4 uM).
ART0380 is effective in vivo in cancers with varying types of ATM, showing modulation of pChk1 Ser345 in tumor xenograft tissues
ART0380 (30 or 50 mg/kg) exhibits tumor growth inhibition in mice bearing ATM LOF Granta-519 xenografts.
ART0380 (100 mg/kg) exhibits tumor regression on patient-derived xenograft (PDX) model harboring a deleterious ATM gene variant (p.E473*), which induced a near total loss of ATM protein.