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 . 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 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. |
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. |
[1]. Yuan B, et al. Poly(ADP-ribose)polymerase (PARP) inhibition and anticancer activity of simmiparib, a new inhibitor undergoing clinical trials. Cancer Lett. 2017 Feb 1;386:47-56.