Abstract 3655: Discovery of SC10914: a highly potent, selective and orally active PARP inhibitor for the treatment of BRCA1/2 deficient cancer

Poly(ADP ribose) polymerase (PARP) inhibitors are a class of anticancer agents that target DNA base excision repair and radio-sensitize cells through impaired DNA repair. When PARP function was impaired, double-stranded DNA breaks accumulated in the absence of effective BER. In cells deficient in homologous recombination (HR), especially in the setting of BRCA-deficiency, these breaks cannot be accurately repaired, resulting in synthetic lethality. Here, we described the identification and characterization of SC10914- a novel, highly potent oral active PARP inhibitor with favorable pharmacokinetic properties. SC10914 is a highly potent PARP inhibitor (PARP1 IC50 = 7.87 nM) with potent anti-proliferative activity against human BRCA deficient tumor cells (MDA-MB-436, BRCA1 deficient, IC50 = 4.03 nM, Capan-1 BRCA2 deficient, IC50 = 11.66 nM) and PTEN deficient tumor cells (HGC-27,PTEN deficient, IC50 = 0.35 μM). Methods and Results: MDA-MB-436 xenograft was derived from human breast cancer cells. Fragments of MDA-MB-436 tumor (approximately 1.5mm3) were implanted into the flank of female BALB/cA nude-mice which were randomized into four groups. Oral treatment with vehicle only, AZD2281 (75 mg/kg qd), SC10914 (25 mg/kg qd) or SC10914 (75 mg/kg qd) were carried out for 21 days. Vc8 xenograft was derived from Chinese hamster Vc8 (BRCA2 deficient) cells, fragments of Vc8 tumor (approximately 1.5mm3) were implanted into the flank of female BALB/cA nude-mice which were randomized into four groups; oral treatment with vehicle only, SC10914 (75 mg/kg qd), SC10914 (25 mg/kg qd) or SC10914 (5 mg/kg qd) were carried out for 21 days. SC10914 showed convincing in vivo efficacy at tolerated doses and resulted in robust dose-dependent anti-tumor efficacy in two xenograft models in nude-mice. Once daily oral treatment of SC10914 led to completed tumor stasis in established MDA-MB-436 xenografts and Vc-8 xenografts. In MDA-MB-436 xenografts, the low dose group (25mg/Kg) had the same efficacy with AZD2281 control group (75mg/Kg). SC10914 displayed a better pharmacokinetics profile compared with AZD2281 on SD rats with a single dosage of 15mg/Kg (oral bioavailability (%): 45.6% vs 26.2%, AUCinf (ng/mL/h): 3123 vs 1721, T1/2 (min): 160 vs 63.6). The pharmacokinetics profile displayed a positive correlation between the dosage of SC10914, drug plasma exposure (AUC0-t) and peak concentration (Cmax) when the dosages were in the range of 40-400mg/Kg. SC10914 has no hERG inhibition (I