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 (HY-10162)。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。
| 生物活性 | Simmiparib is a highly potent and orally activePARP1andPARP2inhibitor withIC50values of 1.75 nM and 0.22 nM, respectively. Simmiparib has more potent PARP1/2 inhibition than its parentOlaparib(HY-10162). Simmiparib induces DNA double-strand breaks (DSB) accumulation and G2/M arrest in homologous recombination repair (HR)-deficient cells, thereby inducingapoptosis. Simmiparib exhibits remarkable anticancer activities in cells and nude mice bearing xenografts[1]. |
| IC50& Target[1] | PARP1 0.74 nM (IC50) | PARP2 0.22 nM (IC50) |
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体外研究
(In Vitro) | 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 IC50s 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. |
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体内研究
(In Vivo) | 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. |
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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | | Powder | -20°C | 3 years | | 4°C | 2 years | | In solvent | -80°C | 6 months | | -20°C | 1 month |
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| 溶解性数据 | In Vitro: DMSO : 100 mg/mL(205.58 mM;ultrasonic and warming and heat to 60℃) 配制储备液 | 1 mM | 2.0558 mL | 10.2792 mL | 20.5584 mL | | 5 mM | 0.4112 mL | 2.0558 mL | 4.1117 mL | | 10 mM | 0.2056 mL | 1.0279 mL | 2.0558 mL |
*请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。
储备液的保存方式和期限：-80℃, 6 months; -20℃, 1 month。-80℃ 储存时，请在 6 个月内使用，-20℃ 储存时，请在 1 个月内使用。 |
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