Thioparib is a next-generation potent, orally bioavailable pan-PARP inhibitor with IC50 of 0.13/0.006 nM (PARP1/2), overcomes multiple PARPi resistance both in vitro and in vivo.
Thioparib has high affinity against multiple PARPs, with an IC50 of 4.7-312 nM for PARP3, TNKS1, TNKS2, PARP6, PARP7, PARP8, PARP11, and PARP12.
Thioparib displays high antitumor activities against PARPi-sensitive and -resistant cells with homologous recombination (HR) deficiency both in vitro and in vivo.
Thioparib is more potent than the clinically approved PARPi Talazoparib and Olaparib.
Thioparib inhibits PARP1-DNA dissociation using DSB FA assays with IC50 of 25.05 nM, 2- and 10-fold greater than talazoparib and olaparib, respectively.
Thioparib shows no significant activity on sirtuins SIRT1, SIRT2, SIRT3, SIRT5, SIRT6, and CD38 at 10 uM.
Thioparib effectively kills HR-deficient tumors in a panel of tumor cell lines harboring BRCA1−/−, BRCA2−/−, PTEN−/−, or EWS-FLI1 gene fusion with average IC50 value of 0.96 nM.
Thioparib (10 mg/kg, oral) exhibited antitumor effect MDA-MB-436 (BRCA1-deficient) xenografts, Thioparib (25 mg/kg, oral) significantly inhibited the growth of Capan-1 xenografts (BRCA2 deficient) in mice.
Thioparib treatment led to PARP1-dependent DNA damage and induced S-phase arrest and apoptosis in JeKo-1 and THP-1 cells.
Thioparib repressed homologous recombination (HR) repair activity but induced excessive RAD51 foci.
Thioparib induced a type I IFN response through PARP7-STING/TBK1 and p38 MAPK pathways.