DS18561882 is a novel, orally active, specific inhibitor of methylenetetrahydrofolate dehydrogenase (MTHFD2), exhibiting an IC50 value of 0.0063 μM[1].
DS18561882(0-10μM; 72h) specifically inhibits MTHFD2 activity and induces cell cycle arrest in HCC38 breast cancer cells, however, it did not induce cell death. Combinatory treatment of Chk1 inhibitor and DS18561882 induces apoptosis synergistically [2]. DS18561882(50 µM; 5days) together with pemetrexed increased the antitumor sensibilities and provided therapeutic advantages in the treatment of Lung adenocarcinoma (LUAD) cells[3].
DS18561882(oral administration; 30, 100 or 300 mg/kg; twice daily) inhibited tumor growth in MDA-MB-231luc tumor mice in a dose-dependent manner, and the tumor was completely suppressed at a dose of 300 mg/kg[1]. DS18561882(100mg/kg; p.o.) can significantly impede the progression of castration-resistant prostate cancer (CRPC) induced by elevated PPFIA4 expression[4].
[1]. Kawai J, Toki T, et,al. 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. doi: 10.1021/acs.jmedchem.9b01113. Epub 2019 Nov 18. PMID: 31638799.
[2]. Lee J, Chen X, et,al. 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. doi: 10.1016/j.bbrc.2021.11.001. Epub 2021 Nov 2. PMID: 34753066.
[3]. Zhao R, Feng T, et,al. PPFIA4 promotes castration-resistant prostate cancer by enhancing mitochondrial metabolism through MTHFD2. J Exp Clin Cancer Res. 2022 Apr 5;41(1):125. doi: 10.1186/s13046-022-02331-3. PMID: 35382861; PMCID: PMC8985307.
DS18561882是一种新型的口服活性特异性亚甲基四氢叶酸脱氢酶(MTHFD2)抑制剂，IC50值为0.0063 μM[1]。
DS18561882(0-10μM; 72h)在HCC38乳腺癌细胞中特异性抑制MTHFD2活性并诱导细胞周期阻滞, 但不诱导细胞死亡。Chk1抑制剂与DS18561882联合处理可协同诱导细胞凋亡[2]。DS18561882(50µM;5days)增加培美曲塞抗肿瘤敏感性，可有利于肺腺癌(LUAD)的治疗[3]。
DS18561882(oral administration; 30, 100 or 300 mg/kg; twice daily)以剂量依赖性的方式抑制MDA-MB-231luc 肿瘤小鼠的肿瘤生长，剂量为300 mg/kg时，小鼠肿瘤被完全抑制[1]。DS18561882(100mg/kg; p.o.)可显著抑制PPFIA4表达升高诱导的去雄抵抗性前列腺癌(CRPC)的进展[4]。