Pamiparib (BGB-290)
(Synonyms: 帕米帕利,BGB-290) 目录号 : GC34071
A PARP1 and PARP2 inhibitor
Cas No.:1446261-44-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Pamiparib is an inhibitor of poly(ADP-ribose) polymerase 1 (PARP1) and PARP2 (IC50s = 1.3 and 0.92 nM, respectively).1 It is selective for PARP1 and PARP2 over PARP3 (IC50 = 0.068 ?M) and other PARP isoforms (IC50s = 2.4->100 ?M), as well as over tankyrase 1 (TNKS1) and TNKS2 (IC50s = 0.23 and 0.14 ?M, respectively). Pamiparib inhibits PARP activity induced by hydrogen peroxide in HeLa cells with an IC50 value of 0.24 nM. It selectively inhibits proliferation of MDA-MB-436 cells expressing mutant BRCA1 and Capan-1 cells expressing mutant BRCA2 (EC50s = 41 and 960 nM, respectively) over MDA-MB-231 cells expressing wild-type BRCA (EC50 = ~9,000 nM). Pamiparib (1.6-6.3 mg/kg twice per day) induces tumor regression in an MDA-MB-436 mouse xenograft model. It also potentiates increases in survival induced by temozolomide in an H209 mouse xenograft model of small cell lung cancer brain metastasis.
1.Xiong, Y., Guo, Y., Liu, Y., et al.Pamiparib is a potent and selective PARP inhibitor with unique potential for the treatment of brain tumorNeoplasia22(9)431-440(2020)
| Cas No. | 1446261-44-4 | SDF | |
| 别名 | 帕米帕利,BGB-290 | ||
| Canonical SMILES | O=C1NN=C2CN(CCC3)[C@@]3(C)C(N4)=C2C5=C4C=C(F)C=C51 | ||
| 分子式 | C16H15FN4O | 分子量 | 298.31 |
| 溶解度 | DMSO : 83.3 mg/mL (279.24 mM) | 储存条件 | Store at -20°C |
| General tips | 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°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.3522 mL | 16.7611 mL | 33.5222 mL |
| 5 mM | 0.6704 mL | 3.3522 mL | 6.7044 mL |
| 10 mM | 0.3352 mL | 1.6761 mL | 3.3522 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Discovery of Pamiparib (BGB-290), a Potent and Selective Poly (ADP-ribose) Polymerase (PARP) Inhibitor in Clinical Development
J Med Chem 2020 Dec 24;63(24):15541-15563.PMID:33264017DOI:10.1021/acs.jmedchem.0c01346.
Poly (ADP-ribose) polymerase (PARP) plays a significant role in DNA repair responses; therefore, this enzyme is targeted by PARP inhibitors in cancer therapy. Here we have developed a number of fused tetra- or pentacyclic dihydrodiazepinoindolone derivatives with excellent PARP enzymatic and cellular PARylation inhibition activities. These efforts led to the identification of pamiparib (BGB-290, 139), which displays excellent PARP-1 and PARP-2 inhibition with IC50 of 1.3 and 0.9 nM, respectively. In a cellular PARylation assay, this compound inhibits PARP activity with IC50 = 0.2 nM. Cocrystal of pamiparib shows similar binding sites with PARP with other PARP inhibitors, but pamiparib is not a P-gp substrate and shows excellent drug metabolism and pharmacokinetics (DMPK) properties with significant brain penetration (17-19%, mice). The compound is currently being investigated in phase III clinical trials as a maintenance therapy in platinum-sensitive ovarian cancer and gastric cancer.
Evaluation of Poly(ADP-ribose) Polymerase Inhibitor, Pamiparib (BGB-290) in Treating Acute Myeloid Leukemia and the Characterization of Its Nanocarrier
J Biomed Nanotechnol 2021 Nov 1;17(11):2165-2175.PMID:34906277DOI:10.1166/jbn.2021.3182.
Despite the continuous improvement of leukemia treatment in the clinic, the overall 5-year disease-free survival of acute myeloid leukemia (AML) is only approximately 30%-60% due to relapse and the refractoriness of AML after traditional chemotherapy. Inhibition of poly(ADP-ribose) polymerase (PARP), a member of the DNA damage repair complex, has a strong antitumor effect in solid tumors. However, the role of PARP in AML remains unclear. We found that high levels of PARP1 and PARP2 were positively related to chemotherapy resistance and poor prognosis in patients with AML. Doxorubicin (DOX)-resistant AML cells highly expressed PAPR1 and PARP2. Knockdown of PARP1 and PARP2, or pharmaceutical inhibition of PARP by the PARP inhibitor (PARPi) BGB-290, significantly enhanced the cytotoxicity of DOX in AML cells due to increased DNA damage. PLGA-loading BGB-290 was properly self-assembled into stable BGB-290@PLGA nanoparticles (NPs), which is uniform particle size and good stability. BGB-290@PLGA is easily uptake by AML cell lines and stays for a long time. Combined with DOX, BGB-290@PLGA can significantly improve the chemosensitivity of AML cell lines. Furthermore, BGB-290 and DOX combination treatment dramatically repressed the onset of leukemia and prolonged the survival of THP-1 xenografted mice. Overall, this study demonstrated that PARPi with traditional chemotherapy could be an efficient therapeutic strategy for AML.
PARP Inhibitor Upregulates PD-L1 Expression and Provides a New Combination Therapy in Pancreatic Cancer
Front Immunol 2021 Dec 17;12:762989.PMID:34975854DOI:10.3389/fimmu.2021.762989.
Despite recent improvements in treatment modalities, pancreatic cancer remains a highly lethal tumor with mortality rate increasing every year. Poly (ADP-ribose) polymerase (PARP) inhibitors are now used in pancreatic cancer as a breakthrough in targeted therapy. This study focused on whether PARP inhibitors (PARPis) can affect programmed death ligand-1 (PD-L1) expression in pancreatic cancer and whether immune checkpoint inhibitors of PD-L1/programmed death 1 (PD-1) can enhance the anti-tumor effects of PARPis. Here we found that PARPi, Pamiparib, up-regulated PD-L1 expression on the surface of pancreatic cancer cells in vitro and in vivo. Mechanistically, Pamiparib induced PD-L1 expression via JAK2/STAT3 pathway, at least partially, in pancreatic cancer. Importantly, Pamiparib attenuated tumor growth; while co-administration of Pamiparib with PD-L1 blockers significantly improved the therapeutic efficacy in vivo compared with monotherapy. Combination therapy resulted in an altered tumor immune microenvironment with a significant increase in windiness of CD8+ T cells, suggesting a potential role of CD8+ T cells in the combination therapy. Together, this study provides evidence for the clinical application of PARPis with anti-PD-L1/PD-1 drugs in the treatment of pancreatic cancer.
Pamiparib: First Approval
Drugs 2021 Jul;81(11):1343-1348.PMID:34287805DOI:10.1007/s40265-021-01552-8.
Pamiparib (PARTRUVIX™; BeiGene Ltd.) is a selective poly (ADP-ribose) polymerase 1 and 2 (PARP1 and PARP2) inhibitor being developed for the treatment of various cancers. Based on the results from the pivotal phase II portion of a phase I/II trial (NCT03333915) Pamiparib was recently approved in China for the treatment of germline BRCA mutation-associated recurrent advanced ovarian, fallopian tube or primary peritoneal cancer previously treated with two or more lines of chemotherapy. This article summarizes the milestones in the development of Pamiparib leading to this first approval.
Pamiparib is a potent and selective PARP inhibitor with unique potential for the treatment of brain tumor
Neoplasia 2020 Sep;22(9):431-440.PMID:32652442DOI:10.1016/j.neo.2020.06.009.
Pamiparib, an investigational Poly (ADP-ribose) polymerase (PARP) inhibitor in clinical development, demonstrates excellent selectivity for both PARP1 and PARP2, and superb anti-proliferation activities in tumor cell lines with BRCA1/2 mutations or HR pathway deficiency (HRD). Pamiparib has good bioavailability and is 16-fold more potent than olaparib in an efficacy study using BRCA1 mutated MDA-MB-436 breast cancer xenograft model. Pamiparib also shows strong anti-tumor synergy with temozolomide (TMZ), a DNA alkylating agent used to treat brain tumors. Compared to other PARP inhibitors, Pamiparib demonstrated improved penetration across the blood brain barrier (BBB) in mice. Oral administration of Pamiparib at a dose as low as 3 mg/kg is sufficient to abrogate PARylation in brain tumor tissues. In SCLC-derived, TMZ-resistant H209 intracranial xenograft model, combination of Pamiparib with TMZ overcomes its resistance and shows significant tumor inhibitory effects and prolonged life span. Our data suggests that combination of Pamiparib with TMZ has unique potential for treatment of brain tumors. Currently, the combination therapy of Pamiparib with TMZ is evaluated in clinical trial [NCT03150862].