Simmiparib
目录号 : GC67962Simmiparib 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。
Cas No.:1551355-46-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
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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.
| Cas No. | 1551355-46-4 | SDF | Download SDF |
| 分子式 | C23H18F4N6O2 | 分子量 | 486.42 |
| 溶解度 | DMSO : 100 mg/mL (205.58 mM; ultrasonic and warming and heat to 60°C) | 储存条件 | Store at -20°C |
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| 10 mM | 0.2056 mL | 1.0279 mL | 2.0558 mL |
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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.PMID:27847302DOI:10.1016/j.canlet.2016.11.010.
Poly(ADP-ribose)polymerase (PARP)1/2 inhibitors have been proved to be clinically effective anticancer drugs. Here we report a new PARP1/2 inhibitor, Simmiparib, displaying apparently improved preclinical anticancer activities relative to the first approved inhibitor olaparib. Simmiparib inhibited PARP1/2 approximately 2-fold more potently than olaparib, with more than 90-fold selectivity over the other tested PARP family members. Simmiparib and olaparib caused similar cellular PARP1-DNA trapping. Simmiparib selectively induced the accumulation of DNA double-strand breaks, G2/M arrest and apoptosis in homologous recombination repair (HR)-deficient cells. Consistently, Simmiparib showed 26- to 235-fold selectivity in its antiproliferative activity against HR-deficient cells over the corresponding isogenic HR-proficient cells. Notably, its antiproliferative activity was 43.8-fold more potent than that of olaparib in 11 HR-deficient cancer cell lines. Simmiparib also potentiated the proliferative inhibition of several conventional anticancer drugs. Simmiparib reduced the poly(ADP-ribose) formation in HR-deficient cancer cells and xenografts. When orally administered to nude mice bearing xenografts, Simmiparib revealed excellent pharmacokinetic properties. Simmiparib caused approximately 10-fold greater growth inhibition than olaparib against HR-deficient human cancer cell- or tissue-derived xenografts in nude mice. Collectively, these findings support the undergoing clinical trials of Simmiparib.
Glycogen synthase kinase 3β inhibition synergizes with PARP inhibitors through the induction of homologous recombination deficiency in colorectal cancer
Cell Death Dis 2021 Feb 15;12(2):183.PMID:33589588DOI:10.1038/s41419-021-03475-4.
Monotherapy with poly ADP-ribose polymerase (PARP) inhibitors results in a limited objective response rate (≤60% in most cases) in patients with homologous recombination repair (HRR)-deficient cancer, which suggests a high rate of resistance in this subset of patients to PARP inhibitors (PARPi). To overcome resistance to PARPi and to broaden their clinical use, we performed high-throughput screening of 99 anticancer drugs in combination with PARPi to identify potential therapeutic combinations. Here, we found that GSK3 inhibitors (GSK3i) exhibited a strong synergistic effect with PARPi in a panel of colorectal cancer (CRC) cell lines with diverse genetic backgrounds. The combination of GSK3β and PARP inhibition causes replication stress and DNA double-strand breaks, resulting in increased anaphase bridges and abnormal spindles. Mechanistically, inhibition or genetic depletion of GSK3β was found to impair the HRR of DNA and reduce the mRNA and protein level of BRCA1. Finally, we demonstrated that inhibition or depletion of GSK3β could enhance the in vivo sensitivity to Simmiparib without toxicity. Our results provide a mechanistic understanding of the combination of PARP and GSK3 inhibition, and support the clinical development of this combination therapy for CRC patients.
Combining 53BP1 with BRCA1 as a biomarker to predict the sensitivity of poly(ADP-ribose) polymerase (PARP) inhibitors
Acta Pharmacol Sin 2017 Jul;38(7):1038-1047.PMID:28414200DOI:10.1038/aps.2017.8.
Over half of patients with BRCA1-deficient cancers do not respond to treatment with poly(ADP-ribose) polymerase (PARP) inhibitors. In this study, we report that a combination of 53BP1 and BRCA1 may serve as a biomarker of PARP inhibitor sensitivity. Based on the mRNA levels of four homologous recombination repair (HR) genes and PARP inhibitor sensitivity, we selected BRCA1-deficient MDA-MB-436 cells to conduct RNA interference. Reducing expression of 53BP1, but not the other three HR genes, was found to lower Simmiparib sensitivity. Additionally, we generated 53BP1-/-/BRCA1-/- clonal variants by the transcription activator-like effector nuclease (TALEN) technique and found that depleting 53BP1 impaired PARP inhibitor sensitivity with a 36.7-fold increase in their IC50 values. Consistent with its effect on PARP inhibitor sensitivity, 53BP1 loss alleviated cell cycle arrest and apoptosis and partially restored HR function. Importantly, 53BP1 depletion dramatically reduced the ability of PARP inhibitors to suppress tumor growth in vivo. The inhibition rate of Simmiparib was 74.16% for BRCA1-deficient MDA-MB-436 xenografts, but only 7.79% for 53BP1/BRCA1-deficient xenografts. Re-expressing 53BP1 in the dual-deficient cells restored PARP inhibitor sensitivity and the levels of HR regulators. Considering that at least 10% of BRCA1-deficient breast and ovarian cancers have reduced expression of 53BP1, using a combination of 53BP1 with BRCA1 as a biomarker for patient selection should reduce the number of patients undergoing futile treatment with PARP inhibitors.
Novel mutations in BRCA2 intron 11 and overexpression of COX-2 and BIRC3 mediate cellular resistance to PARP inhibitors
Am J Cancer Res 2020 Sep 1;10(9):2813-2831.PMID:33042619doi
Several poly(ADP ribose) polymerase (PARP) inhibitors (PARPi) have been approved for cancer therapy; however, intrinsic and acquired resistance has limited their efficacy in the clinic. In fact, cancer cells have developed multiple mechanisms to overcome PARPi cytotoxicity in even a single cancer cell. In this study, we generated three PARPi-resistant BRCA2-deficient pancreatic Capan-1 variant cells using olaparib (Capan-1/OP), talazoparib (Capan-1/TP), and Simmiparib (Capan-1/SP). We identified novel mutations in intron 11 of BRCA2, which resulted in the expression of truncated BRCA2 splice isoforms. Functional studies revealed that only a fraction (32-49%) of PARPi sensitivity could be rescued by depletion of BRCA2 isoforms. In addition, the apoptosis signals (phosphatidylserine eversion, caspase 3/7/8/9 activation, and mitochondrial membrane potential loss) were almost completely abrogated in all PARPi-resistant variants. Consistently, overexpression of the anti-apoptotic proteins cyclooxygenase 2 (COX-2) and baculoviral IAP repeat-containing 3 (BIRC3) occurred in these variants. Depletion of COX-2 or BIRC3 significantly reduced apoptotic resistance in the PARPi-resistant sublines and reversed PARPi resistance by up to 70-72%. Furthermore, exogenous addition of prostaglandin E2, a major metabolic product of COX-2, inhibited PARPi-induced apoptotic signals; however, when combined with the BIRC3 inhibitor LCL161, there was significantly enhanced sensitivity of the resistant variants to PARPi. Finally, PARPi treatment or PARP1 depletion led to a marked increase in the mRNA and protein levels of COX-2 and BIRC3, indicating that PARP1 is a negative transcriptional regulator of these proteins. Together, our findings demonstrated that during the chronic treatment of cells with a PARPi, both BRCA2 intron 11 mutations and COX-2/BIRC3-mediated apoptotic resistance led to PARPi resistance in pancreatic Capan-1 cells.
Acquired resistance of phosphatase and tensin homolog-deficient cells to poly(ADP-ribose) polymerase inhibitor and Ara-C mediated by 53BP1 loss and SAMHD1 overexpression
Cancer Sci 2018 Mar;109(3):821-831.PMID:29274141DOI:10.1111/cas.13477.
With increasing uses of poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) for cancer therapy, understanding their resistance is becoming urgent. However, acquired PARPi resistance in the phosphatase and tensin homolog (PTEN)-deficient background is poorly understood. We generated 3 PARPi-resistant PTEN-deficient glioblastoma U251 variants separately with olaparib (U251/OP), talazoparib (U251/TP) and Simmiparib (U251/SP). These variants displayed consistent resistance (2.46-71.78-fold) to all 5 PARPi, including niraparib and rucaparib, and showed higher degrees of resistance to the PARPi to which the parental cells were more sensitive. The resistance was characteristic of fast emergence and high stability. However, the resistance acquirement did not cause an increasingly aggressive phenotype. The resistance was not correlated to various factors, including PTEN mutations. The PARPi-treated variants produced less γH2AX and G2/M arrest. Consistently, loss of 53BP1 occurred in all variants and its compensation enhanced their sensitivity to PARPi by approximately 76%. The variants revealed slightly different cross-resistance profiles to 13 non-PARPi anticancer drugs. All were resistant to Ara-C (6-8-fold) but showed differential resistance to 5-fluorouracil, gemcitabine and paclitaxel. Almost no resistance was observed to the rest drugs, including cisplatin. SAMHD1 was overexpressed in all the variants and its knockout completely restored their sensitivity to Ara-C but did not affect their PARPi sensitivity. The present study demonstrates a consistent resistance profile to PARPi and a unique cross-resistance profile to non-PARPi drugs in different PARPi-resistant U251 cells and reveals 53BP1 loss and SAMHD1 overexpression as the primary mechanisms responsible for their resistance to PARPi and Ara-C, respectively. These effects probably result from heritable gene change(s) caused by persistent PARPi exposure.