DS18561882
目录号 : GC38906
DS18561882 是一种高效的，对酶具有高选择性的亚甲基四氢叶酸脱氢酶 2 ( MTHFD2) 抑制剂，IC50 值为 0.0063 μM。DS18561882 抑制 MTHFD2 的 IC50 值是0.57 μM。DS18561882 具有良好的口服药代动力学特性。
Cas No.:2227149-22-4
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
DS18561882 is a highly potent, isozyme-selective methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) inhibitor with an IC50 value of 0.0063 μM. DS18561882 also has inhibitory effect on MTHFD1 (IC50=0.57 μM). DS18561882 exhibits a good oral pharmacokinetic profile[1].
DS18561882 (0-150 nM) gives the lowest GI50 value (140 nM) against the MDA-MB-231 cell line[1].
DS18561882 (oral administration; 30, 100 or 300 mg/kg; twice daily) inhibits tumor growth inhibition with a dose-dependent manner, the tumor is completely inhibited (TGI: 67%) at the dose of 300 mg/kg in mice[1].DS18561882 (oral administration; 10, 30, 100, or 300 mg/kg) has a good oral pharmacokinetic profile, including ACU (64.6, 264, 726 μg.h/ml ); Cmax (11.4, 56.5, 90.1 μg/ml); t1/2 (2.21, 2.16, 2.32 hours) for 30 mg/kg; 100mg/kg; 200 mg/kg, respectively[1].DS18561882 is suspended in a 0.5% (w/v) methyl cellulose 400 solution in this article[1]. Animal Model: Five week old female BALB/cAJcl-nu/nu mice with MDA-MB-231 luc tumor cells (4 × 106 cells/mouse)[1]
[1]. Kawai J, et al. Discovery of a Potent, Selective, and Orally Available MTHFD2 Inhibitor (DS18561882) with In Vivo Anti-Tumor Activity. J Med Chem. 2019 Oct 22.
| Cas No. | 2227149-22-4 | SDF | |
| Canonical SMILES | CS(=O)(NC1=CC=C(C(N2CCC(C3=CC=C(N4C[C@H](C)N(C)CC4)C(C)=C3O5)=C(C5=O)C2)=O)C=C1OC(F)(F)F)=O | ||
| 分子式 | C28H31F3N4O6S | 分子量 | 608.63 |
| 溶解度 | DMSO: 250 mg/mL (410.76 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。 |
||
| 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 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 1.643 mL | 8.2152 mL | 16.4303 mL |
| 5 mM | 0.3286 mL | 1.643 mL | 3.2861 mL |
| 10 mM | 0.1643 mL | 0.8215 mL | 1.643 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。
PPFIA4 promotes castration-resistant prostate cancer by enhancing mitochondrial metabolism through MTHFD2
J Exp Clin Cancer Res 2022 Apr 5;41(1):125.PMID:35382861DOI:10.1186/s13046-022-02331-3.
Background: The development of castration-resistant prostate cancer (CRPC) remains a major obstacle in the treatment of prostate cancer (PCa). Dysregulated mitochondrial function has been linked to the initiation and progression of diverse human cancers. Deciphering the novel molecular mechanisms underlying mitochondrial function may provide important insights for developing novel therapeutics for CRPC. Methods: We investigate the expression of the protein tyrosine phosphatase receptor type F polypeptide interacting protein alpha 4 (PPFIA4) using public datasets and tumor specimens from PCa cases by immunohistochemistry. Gain- and loss-of-function studies are performed in PCa cell lines and mouse models of subcutaneous xenograft to characterize the role of PPFIA4 in CRPC. Gene expression regulation is evaluated by a series of molecular and biochemical experiments in PCa cell lines. The therapeutic effects of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) inhibitor combined enzalutamide are assessed using in vitro functional assays and in vivo mouse models. Results: We show that the increase of PPFIA4 exacerbates aggressive phenotype resembling CRPC. A fraction of PPFIA4 localizes to mitochondria and interacts with MTHFD2, a key enzyme for one-carbon metabolism. Androgen deprivation increases the translocation of PPFIA4 into mitochondria and increases the interaction between PPFIA4 and MTHFD2, which result in the elevation of tyrosine phosphorylated MTHFD2. Consequently, the levels of NADPH synthesis increase, resulting in protection against androgen deprivation-induced mitochondrial dysfunction, as well as promotion of tumor growth. Clinically, PPFIA4 expression is significantly increased in CRPC tissues compared with localized PCa ones. Importantly, an MTHFD2 inhibitor, DS18561882, combined with enzalutamide can significantly inhibit CRPC cell proliferation in vitro and tumor growth in vivo. Conclusion: Overall, our findings reveal a PPFIA4-MTHFD2 complex in mitochondria that links androgen deprivation to mitochondrial metabolism and mitochondrial dysfunction, which suggest a potential strategy to inhibit CRPC progression.
Discovery of a Potent, Selective, and Orally Available MTHFD2 Inhibitor (DS18561882) with in Vivo Antitumor Activity
J Med Chem 2019 Nov 27;62(22):10204-10220.PMID:31638799DOI:10.1021/acs.jmedchem.9b01113.
We report the discovery of a potent and isozyme-selective MTHFD2 inhibitor, DS18561882 (2). Through investigation of the substituents on our tricyclic coumarin scaffold (1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one), MTHFD2 inhibitory activity was shown to be elevated by incorporating an amine moiety at the 8-position and a methyl group at the 7-position of the initial lead 1. X-ray structure analysis revealed that a key interaction for enhanced potency was salt bridge formation between the amine moiety and the diphosphate linker of an NAD+ cofactor. Furthermore, ortho-substituted sulfonamide in place of benzoic acid of 1 significantly improved cell permeability and cell-based growth inhibition against a human breast cancer cell line. The thus-optimized DS18561882 showed the strongest cell-based activity (GI50 = 140 nM) in the class, a good oral pharmacokinetic profile, and thereby tumor growth inhibition in a mouse xenograft model upon oral administration.
A novel oral inhibitor for one-carbon metabolism and checkpoint kinase 1 inhibitor as a rational combination treatment for breast cancer
Biochem Biophys Res Commun 2021 Dec 20;584:7-14.PMID:34753066DOI:10.1016/j.bbrc.2021.11.001.
Patients with triple-negative breast cancer have a poor prognosis as only a few efficient targeted therapies are available. Cancer cells are characterized by their unregulated proliferation and require large amounts of nucleotides to replicate their DNA. One-carbon metabolism contributes to purine and pyrimidine nucleotide synthesis by supplying one carbon atom. Although mitochondrial one-carbon metabolism has recently been focused on as an important target for cancer treatment, few specific inhibitors have been reported. In this study, we aimed to examine the effects of DS18561882 (DS18), a novel, orally active, specific inhibitor of methylenetetrahydrofolate dehydrogenase (MTHFD2), a mitochondrial enzyme involved in one-carbon metabolism. Treatment with DS18 led to a marked reduction in cancer-cell proliferation; however, it did not induce cell death. Combinatorial treatment with DS18 and inhibitors of checkpoint kinase 1 (Chk1), an activator of the S phase checkpoint pathway, efficiently induced apoptotic cell death in breast cancer cells and suppressed tumorigenesis in a triple-negative breast cancer patient-derived xenograft model. Mechanistically, MTHFD2 inhibition led to cell cycle arrest and slowed nucleotide synthesis. This finding suggests that DNA replication stress occurs due to nucleotide shortage and that the S-phase checkpoint pathway is activated, leading to cell-cycle arrest. Combinatorial treatment with both inhibitors released cell-cycle arrest, but induced accumulation of DNA double-strand breaks, leading to apoptotic cell death. Collectively, a combination of MTHFD2 and Chk1 inhibitors would be a rational treatment option for patients with triple-negative breast cancer.