Simmiparib 是一种高效且具有口服活性的PARP1和PARP2抑制剂，IC50分别为 1.75 nM 和 0.22 nM。Simmiparib 对 PARP1/2 的抑制作用强于其母体化合物Olaparib。在同源重组修复 (HR) 缺陷细胞中，Simmiparib 诱导 DNA 双链断裂 (DSB) 积累和 G2/M 阻滞，从而诱导细胞凋亡 (Apoptosis)。Simmiparib 在细胞和裸鼠移植瘤模型中都表现出显著的抗癌活性。

Simmiparib is a highly potent and orally active PARP1 and PARP2 inhibitor with IC 50 values of 1.75 nM and 0.22 nM, respectively. Simmiparib has more potent PARP1/2 inhibition than its parent Olaparib. Simmiparib induces DNA double-strand breaks (DSB) accumulation and G2/M arrest in homologous recombination repair (HR)-deficient cells, thereby inducing apoptosis. Simmiparib exhibits remarkable anticancer activities in cells and nude mice bearing xenografts [1].

Simmiparib (0-10 μM; 3 days) exhibits anti-proliferative activity against various cancer cells [1]. Simmiparib (0-10 μM; 48 h) induces typical G2/M arrest in Capan-1 cells [1]. Simmiparib (0.1-2 μM; 24 h) induces apoptosis in MDA-MB-436 and V-C8 (BRCA2 -/- ) cells, and increases dose-dependently the levels of γH2AX [1]. Simmiparib (1-10 μM; 48 h or 72 h) increases the phosphorylation levels of Chk1 and Chk2 and the protein levels of p-Cyclin B1 (S147), Cyclin B1, p-CDK1 (Y15) and CDK1 [1]. Cell Proliferation Assay [1] Cell Line: Various cancer cells harboring deficient BRCA1, BRCA2, PTEN and EWS-FLI1 Concentration: 0-10 μM Incubation Time: 3 days Result: Exhibited anti-proliferative activity against MDA-MB-436 (BRCA1 -/- ), RD-ES (EWS-FLI1), DoTc2-4510 (BRCA2 -/- ), Capan-1 (BRCA2 -/- ) and U251 (PTEN -/- ) with IC 50 s of 0.2 nM, 4.6 nM, 20 nM, 21 nM and 36 nM, respectively. Cell Cycle Analysis [1] Cell Line: Capan-1 cells Concentration: 0, 1, 3 and 10 μM Incubation Time: 48 h Result: Induced typical G2/M arrest in a concentration-dependent manner. Apoptosis Analysis [1] Cell Line: MDA-MB-436 Concentration: 0.1 and 1 μM Incubation Time: 24 h Result: Led to 39.64% and 42.98% apoptosis at 0.1 and 1 μM, respectively. Increased dose-dependently the levels of γH2AX. Apoptosis Analysis [1] Cell Line: V-C8 (BRCA2 -/- ) Concentration: 0.5 and 2 μM Incubation Time: 24 h Result: Caused more than 57% apoptosis. Western Blot Analysis [1] Cell Line: Capan-1 Concentration: 1 and 10 μM Incubation Time: 48 h or 72 h Result: Increased the phosphorylation levels of Chk1 and Chk2 but did not change the levels of the corresponding total proteins. Increased the protein levels of p-Cyclin B1 (S147), Cyclin B1, p-CDK1 (Y15) and CDK1.

Simmiparib (2, 4 and 8 mg/kg; p.o.; qd, for 14 days) inhibits the growth of tumor in V-C8 (BRCA2 -/- ) and MDA-MB-436 (BRCA2 -/- ) xenograft mice models [1]. Simmiparib (10 and 50 mg/kg; p.o.; qd, for 42 days) inhibits the growth of BRCA1-mutated breast cancer in xenograft mice model [1]. Animal Model: Female BALB/cA nude mice (Subcutaneously injected with BRCA2 -/- V-C8 cells and BRCA2 -/- MDA-MB-436 cells) [1] Dosage: 2, 4 and 8 mg/kg Administration: p.o.; qd, for 14 days Result: Apparently inhibited the growth of the V-C8 tumor with an inhibition rate of 74.53% at 8 mg/kg. Suppressed the growth of the BRCA1-deficient MDA-MB-436 xenografts in a dose-dependent manner with its average inhibition rates of 64.93, 82.98 and 85.79% at 2, 4 and 8 mg/kg. Did not cause significant loss of body weight. Animal Model: Female BALB/cA nude mice (Subcutaneously injected with cancer cells derived from BRCA1-mutated BR-05-0028 breast cancer tissue) [1] Dosage: 10 and 50 mg/kg Administration: p.o.; qd, for 42 days Result: Elicited dose-dependent growth inhibition with the inhibition rate of 76.73% and 93.82% at 10 mg/kg and 50 mg/kg, respectively.

1551355-46-4

C23H18F4N6O2

486.42

(< 1 mg/ml refers to the product slightly soluble or insoluble )
Powder: -20°C for 3 years
In solvent: -80°C for 2 years