AD1058 is a highly potent, selective, brain-penetrant ATR inhibitor with IC50 of 1.6 nM.
AD1058 displays excellent selectivity against 15 kinases belonging to six kinase subfamilies (mTOR from PIKK subfamily; AMPKα2β1γ1, DRAK2, BRSK2, ARK5 from CAMK subfamily; CDK2 from CMGC subfamily; IRAK4 from TKL subfamily; FLT3, LCK, MER, LYN, BTK, ABL1, JAK1 from TK subfamily; Aurora B from Aurora subfamily).
AD1058 exhibits potent in vitro antiproliferative activities against a panel of tumor cell lines (B-cell lymphoma: Granta-519 (IC50=0.19 uM), OCI-Ly10, SU-DHL4, ovary cancer: A2780, colorectal cancer: LoVo, HCT116, HT-29, DLD1, lung cancer: NCI-H446, pancreatic cancer: Capan-1, and prostate cancer: PC-3).
AD1058 effectively inhibits Niraparib-induced CHK1 phosphorylation in Granta-519, more potently than AZ20 or AZD6738 at 2 uM. AD1058 (25 and/or 50 mg/kg) exhibits significant inhibition of tumor growth in CB17-SCID mice bearing xenograft tumor inoculating Granta-519, effectively improves the antitumor effect of the clinically ionizing radiotherapy.