Simmiparib

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

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。

Simmiparib is a highly potent and orally active PARP1 and PARP2 inhibitor with IC50 values of 1.75 nM and 0.22 nM, respectively. Simmiparib has more potent PARP1/2 inhibition than its parent Olaparib (HY-10162). 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.

Simmiparib (0-10 μM; 3 days) exhibits anti-proliferative activity against various cancer cells.Simmiparib (0-10 μM; 48 h) induces typical G2/M arrest in Capan-1 cells.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.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.Cell Proliferation Assay 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 Cell Line:Capan-1 cell Concentration:0, 1, 3 and 10 μM Incubation Time:48 h Result:Induced typical G2/M arrest in a concentration-dependent manner.Apoptosis Analysis 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 Cell Line:V-C8 (BRCA2-/-) Concentration: 0.5 and 2 μM Incubation Time:24 h Result:Caused more than 57% apoptosis.Western Blot Analysis 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.Simmiparib (10 and 50 mg/kg; p.o.; qd, for 42 days) inhibits the growth of BRCA1-mutated breast cancer in xenograft mice model.Animal Model:Female BALB/cA nude mice (Subcutaneously injected with BRCA2-/- V-C8 cells and BRCA2-/- MDA-MB-436 cells) 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) 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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Apoptosis

Apoptosis

Apoptosis | PARP

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1551355-46-4

486.42

C23H18F4N6O2

>98% (HPLC)

In Vitro:?DMSO 中的溶解度 : 100 mg/mL (205.58 mM; 超声助溶 (<60°C)

CC1CN(Cc2nnc(n12)C(F)(F)F)C(=O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F

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(-20℃)

With Ice Pack

≥ 2 years