PARP1/2/TNKS1/2-IN-1 is a potent and selective dual PARP-1/2 and TNKS1/2 inhibitor with IC50 values of 0.25 nM, 1.2 nM, 13.5 nM and 4.15 nM for PARP-1, PARP-2, TNKS1 and TNKS2, respectively. PARP1/2/TNKS1/2-IN-1 suppresses Wnt/β-catenin signaling, decreases pADPr and BRCA1 expression, induces DNA damage, promotes apoptosis, and arrests the cell cycle at the G2/M phase. PARP1/2/TNKS1/2-IN-1 can be used for the study of on colorectal cancer and triple-negative breast cancer [1].
In Vivo, PARP1/2/TNKS1/2-IN-1 (compound I-9) (25-100 mg/kg; i.p.; once daily; for 28 days) has antitumor activity in HCT116 cell-derived xenograft mouse model[1]. PARP1/2/TNKS1/2-IN-1 (500 mg/kg; i.p.; single dose) shows no obvious acute toxicity or intestinal toxicity in Sprague-Dawley rats[1].
In Vitro, PARP1/2/TNKS1/2-IN-1 (compound I-9) inhibits PARP-1, PARP-2, TNKS1 and TNKS2 with IC50 values of 0.25 nM, 1.2 nM, 13.5 nM and 4.15 nM, respectively; it also inhibits PARP-7, PARP-10, PARP-12 and PARP-14 with IC50 values of 15.0 nM, 140.0 nM, 371.0 nM and 1369.0 nM, respectively, and shows weak or no inhibitory activity against 208 tested kinases at 1 μM[1]. PARP1/2/TNKS1/2-IN-1 (0.01-10 μM; 7 days) inhibits MDA-MB-231, HCT116 and MDA-MB-468 cancer cell proliferation, with IC50 values of 0.87 μM, 0.75 μM and 0.09 μM, respectively[1]. PARP1/2/TNKS1/2-IN-1 shows low cytotoxicity in AML12 cells, with a CC50 of 117.47 μM[1]. PARP1/2/TNKS1/2-IN-1 (10 μM) modulates PARP- and Wnt/β-catenin-related signaling in HCT116 cells by decreasing pADPr, active β-catenin, total β-catenin, cyclin D1 and BRCA1 expression, and increasing axin2 expression[1]. PARP1/2/TNKS1/2-IN-1 (1 μM; 72 h) reduces RAD51 foci formation and increases γH2AX nuclear foci in HCT116 cells[1]. PARP1/2/TNKS1/2-IN-1 (1, 5 μM; 3 days) promotes apoptosis and arrests the cell cycle at the G2/M phase in HCT116 cells[1].
References:
[1]. Xu Y, et al. Rational design, synthesis and biological evaluation of dual PARP-1/2 and TNKS1/2 inhibitors for cancer therapy. Eur J Med Chem. 2022 Jul 5;237:114417.
In Vivo, PARP1/2/TNKS1/2-IN-1 (compound I-9) (25-100 mg/kg; i.p.; once daily; for 28 days) has antitumor activity in HCT116 cell-derived xenograft mouse model[1]. PARP1/2/TNKS1/2-IN-1 (500 mg/kg; i.p.; single dose) shows no obvious acute toxicity or intestinal toxicity in Sprague-Dawley rats[1].
In Vitro, PARP1/2/TNKS1/2-IN-1 (compound I-9) inhibits PARP-1, PARP-2, TNKS1 and TNKS2 with IC50 values of 0.25 nM, 1.2 nM, 13.5 nM and 4.15 nM, respectively; it also inhibits PARP-7, PARP-10, PARP-12 and PARP-14 with IC50 values of 15.0 nM, 140.0 nM, 371.0 nM and 1369.0 nM, respectively, and shows weak or no inhibitory activity against 208 tested kinases at 1 μM[1]. PARP1/2/TNKS1/2-IN-1 (0.01-10 μM; 7 days) inhibits MDA-MB-231, HCT116 and MDA-MB-468 cancer cell proliferation, with IC50 values of 0.87 μM, 0.75 μM and 0.09 μM, respectively[1]. PARP1/2/TNKS1/2-IN-1 shows low cytotoxicity in AML12 cells, with a CC50 of 117.47 μM[1]. PARP1/2/TNKS1/2-IN-1 (10 μM) modulates PARP- and Wnt/β-catenin-related signaling in HCT116 cells by decreasing pADPr, active β-catenin, total β-catenin, cyclin D1 and BRCA1 expression, and increasing axin2 expression[1]. PARP1/2/TNKS1/2-IN-1 (1 μM; 72 h) reduces RAD51 foci formation and increases γH2AX nuclear foci in HCT116 cells[1]. PARP1/2/TNKS1/2-IN-1 (1, 5 μM; 3 days) promotes apoptosis and arrests the cell cycle at the G2/M phase in HCT116 cells[1].
References:
[1]. Xu Y, et al. Rational design, synthesis and biological evaluation of dual PARP-1/2 and TNKS1/2 inhibitors for cancer therapy. Eur J Med Chem. 2022 Jul 5;237:114417.