Forodesine (BCX-1777 freebase)
(Synonyms: 呋咯地辛; BCX-1777; Immucillin-H) 目录号 : GC33029A nucleoside analog and PNP inhibitor
Cas No.:209799-67-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Forodesine is a purine nucleoside analog and purine nucleoside phosphorylase (PNP) inhibitor (IC50s = 1.19, 0.48, 1.24, 0.66, and 1.57 nM for human, mouse, rat, monkey, and dog PNP, respectively).1 It inhibits phytohemagglutinin A-, mixed lymphocyte reaction-, or IL-2-induced proliferation of isolated human peripheral blood lymphocytes (PBLs; IC50s = <0.1-0.38 ?M) in the presence, but not absence, of 2’-deoxyguanosine (dGuo). Forodesine inhibits proliferation of CEM-SS T cell acute lymphoblastic leukemia (T-ALL) cells.2 In vivo, forodesine (10 mg/kg) prolongs survival in the hu-PBL-SCID mouse model of xenogeneic graft versus host disease (GVHD).1
1.Bantia, S., Miller, P.J., Parker, C.D., et al.Purine nucleoside phosphorylase inhibitor BCX-1777 (immucillin-H)-a novel potent and orally active immunosuppressive agentInt. Immunopharmacol.1(6)1199-1210(2001) 2.Al-Kali, A., Gandhi, V., Ayoubi, M., et al.Forodesine: Review of preclinical and clinical dataFuture Oncol.6(8)1211-1217(2010)
| Cas No. | 209799-67-7 | SDF | |
| 别名 | 呋咯地辛; BCX-1777; Immucillin-H | ||
| Canonical SMILES | O=C1C(NC=C2[C@@H]3N[C@H](CO)[C@@H](O)[C@H]3O)=C2NC=N1 | ||
| 分子式 | C11H14N4O4 | 分子量 | 266.25 |
| 溶解度 | PBS (pH 7.2): 5 mg/ml | 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 | 3.7559 mL | 18.7793 mL | 37.5587 mL |
| 5 mM | 0.7512 mL | 3.7559 mL | 7.5117 mL |
| 10 mM | 0.3756 mL | 1.8779 mL | 3.7559 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。
Forodesine in the treatment of cutaneous T-cell lymphoma
Expert Opin Investig Drugs 2017 Jun;26(6):771-775.PMID:28447489DOI:10.1080/13543784.2017.1324569.
Cutaneous T-cell lymphoma (CTCL) is characterized by the accumulation of neoplastic CD4+ T lymphocytes in the skin. Given the lack of curative treatments for CTCL, there is a significant need for new, superior therapies. Forodesine is a transition-state analogue that inhibits purine nucleoside phosphorylase. Because it selectively targets T lymphocytes, it represents a drug of interest for the treatment of CTCL. Areas covered: Phase I/II dose-ranging studies of intravenous (IV) and oral Forodesine demonstrated its activity, safety, and tolerability for refractory CTCL. Response rates were 31% and 27%, respectively. No dose-limiting toxicities were observed. These studies were followed by a phase II trial of oral Forodesine 200 mg daily. This oral formulation showed only partial activity, with a response rate of 11%, likely attributable to underdosing. Common adverse events in these trials included infection, fatigue, peripheral edema, nausea, pruritus, headache, and insomnia. Expert opinion: IV and oral formulations of Forodesine have demonstrated partial activity and an acceptable safety profile in patients with refractory CTCL. A higher oral dose, or sequential therapy consisting of IV Forodesine followed by maintenance oral Forodesine, may be more effective. With proper dosing, Forodesine may emerge as a safe and effective treatment for refractory CTCL.
Forodesine in the treatment of relapsed/refractory peripheral T-cell lymphoma: an evidence-based review
Onco Targets Ther 2018 Apr 20;11:2287-2293.PMID:29719411DOI:10.2147/OTT.S140756.
T-cell lymphoma is a rare hematologic malignancy with an incidence rate between 10% and 20% of that of non-Hodgkin lymphomas. Patients with peripheral T-cell lymphoma (PTCL) generally have a poor prognosis when treated with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)/CHOP-like chemotherapy; once relapse occurs, it is mostly regarded as an incurable disease. To overcome the chemorefractoriness of PTCL, several novel agents have been developed. Since the first approval of pralatrexate, a dihydrofolate reductase inhibitor, for relapsed/refractory PTCL by the US Food and Drug Administration, several new agents, such as romidepsin (histone deacetylase inhibitor), brentuximab vedotin (antibody-drug conjugate targeting CD30), chidamide (histone deacetylase inhibitor), and mogamulizumab (anti-CC chemokine receptor 4 monoclonal antibody), have been approved as a therapeutic option for relapsed/refractory PTCL in several countries, including the US, Europe, China, and Japan. Forodesine is a novel, potent purine nucleoside phosphorylase inhibitor that is effective against T-cell malignancies. Although the clinical development of Forodesine was discontinued in the US and Europe, a multicenter Phase I/II study of oral Forodesine for relapsed PTCL was recently completed in Japan. The overall response rate was 24% (10 of 41 patients), which included four patients with complete response. In general, the toxicity of Forodesine is manageable. As the study met the primary end point, Forodesine was approved for the treatment of relapsed/refractory PTCL in Japan in March 2017, which was the first approval of Forodesine in the world. As Forodesine is an oral formulation, it is more convenient than other novel intravenous agents approved for PTCL. However, it is necessary to appropriately manage opportunistic infections and secondary lymphomas possibly associated with long-lasting lymphocytopenia caused by Forodesine. In this manuscript, we have summarized the currently available evidence for Forodesine and discussed the clinical implications for PTCL treatment.
Forodesine (BCX-1777, Immucillin H)--a new purine nucleoside analogue: mechanism of action and potential clinical application
Mini Rev Med Chem 2007 Sep;7(9):976-83.PMID:17897085DOI:10.2174/138955707781662636.
Recently a few new purine nucleoside analogues (PNA) have been synthesized and introduced into preclinical and clinical trials. The transition-state theory has led to the design of 9-deazanucleotide analogues that are purine nucleoside phosphorylase (PNP) inhibitors, termed immucillins. Among them the most promising results have been obtained with Forodesine. Forodesine (BCX-1777, Immucillin H, 1-(9-deazahypoxanthin)-1,4-dideoxy-1,4-imino-D-ribitol) has carbon-carbon linkage between a cyclic amine moiety that replaces ribose and 9-deaza-hypixanthine. The drug is a novel T-cell selective immunosuppressive agent which in the presence of 2'-deoxyguanosine (dGuo) inhibits human lymphocyte proliferation activated by various agents such as interleukin-2 (IL-2), mixed lymphocyte reaction and phytohemagglutinin. In the mechanism of Forodesine action two enzymes are involved: PNP and deoxycytidine kinase (dCK). PNP catalyzes the phosphorolysis of dGuo to guanine (Gu) and 2'-deoxyribose-1-phosphate, whereas dCK converts dGuo to deoxyguanosino-5'-monophosphate (dGMP) and finally to deoxyguanosino-5'-triphosphate (dGTP). The affinity of dGuo is higher for PNP than for dCK. Nevertheless, if PNP is blocked by Forodesine, plasma dGuo is not cleaved to Gu, but instead it is intracellularly converted to dGTP by high dCK activity, which leads to inhibition of ribonucleotide reductase (RR), an enzyme required for DNA synthesis and cell replication, which eventually results in apoptosis. Forodesine is active in some experimental tumors in mice, however it could be used for the treatment of human T-cell proliferative disorders and it is undergoing phase II clinical trials for the treatment of T-cell non-Hodgkin's lymphoma, which includes cutaneous T-cell lymphoma (CTCL). Moreover, recent preclinical and clinical data showed activity of Forodesine in B-cell acute lympholastic leukemia (ALL).
Forodesine: review of preclinical and clinical data
Future Oncol 2010 Aug;6(8):1211-7.PMID:20799866DOI:10.2217/fon.10.83.
Purine nucleoside phosphorylase (PNP) is an important catalytic enzyme in the purine salvage pathway; its deficiency is associated with T-cell lymphopenia and with humoral deficiency. This clinical observation led to the investigation of PNP inhibitors and their possible clinical application in the management of hematologic malignancies, notably those of T-cell lineage. Forodesine is the most potent of the PNP inhibitors. Its effect appears to be linked to increased 2 -deoxyguanosine levels in plasma, which in turn is converted to 2 -deoxyguanosine triphosphate in target cells and disrupts DNA synthesis. Several preclinical studies have shown Forodesine's effect against lymphocytes in vitro and in vivo, and these findings have led to several Phase I/II studies in patients with lymphoid neoplasms. Early clinical trials show that Forodesine has promise as a single agent for the treatment of relapsed/refractory hematologic malignancies, and combination therapies might be warranted to improve clinical results.
SAMHD1 Limits the Efficacy of Forodesine in Leukemia by Protecting Cells against the Cytotoxicity of dGTP
Cell Rep 2020 May 12;31(6):107640.PMID:32402273DOI:10.1016/j.celrep.2020.107640.
The anti-leukemia agent Forodesine causes cytotoxic overload of intracellular deoxyguanosine triphosphate (dGTP) but is efficacious only in a subset of patients. We report that SAMHD1, a phosphohydrolase degrading deoxyribonucleoside triphosphate (dNTP), protects cells against the effects of dNTP imbalances. SAMHD1-deficient cells induce intrinsic apoptosis upon provision of deoxyribonucleosides, particularly deoxyguanosine (dG). Moreover, dG and Forodesine act synergistically to kill cells lacking SAMHD1. Using mass cytometry, we find that these compounds kill SAMHD1-deficient malignant cells in patients with chronic lymphocytic leukemia (CLL). Normal cells and CLL cells from patients without SAMHD1 mutation are unaffected. We therefore propose to use Forodesine as a precision medicine for leukemia, stratifying patients by SAMHD1 genotype or expression.