DDD85646 is a potent inhibitor of Trypanosoma brucei N-myristoyltransferase (NMT), exhibiting half-maximal inhibitory concentration (IC₅₀) values of 2nM against T. brucei NMT (TbNMT) and 4nM against human NMT (hNMT)[1]. DDD85646 effectively inhibits the proliferation of trypanosomes[2], and also demonstrates antiviral activity by suppressing viral replication[3-4].
In vitro, co-treatment of acute monocytic leukemia THP-1 cells with DDD85646 (10μM) and the ferroptosis inducer Erastin (10μM) for 36 hours enhanced susceptibility to ferroptosis—characterized by lipid peroxidation, glutathione depletion, and mitochondrial shrinkage—via inhibition of FSP1 localization to the cell membrane[5]. Pretreatment of A549, HEK293T, HAP1, and Vero E6 cells with DDD85646 (0.1–10μM) for 1–5 hours, followed by infection with lymphocytic choriomeningitis virus (LCMV; MOI=0.05–1) for 24–72 hours, significantly suppressed viral protein expression, reduced viral titers, and decreased the number of infected cells[6].
In vivo, oral administration of DDD85646 (12.5–50mg/kg) twice daily for 4 days to mice infected with Trypanosoma brucei strains S427 or STIB900 resulted in significant clearance of parasites from peripheral blood[7]. Subcutaneous injection of DDD85646 (20–60mg/kg) once daily or every other day for 7–16 days in mice bearing DOHH2 or BL2 lymphoma xenografts led to significant suppression of tumor growth and induction of complete tumor regression[8].
References:
[1] Spinks D, Smith V, Thompson S, et al. Development of Small-Molecule Trypanosoma brucei N-Myristoyltransferase Inhibitors: Discovery and Optimisation of a Novel Binding Mode. ChemMedChem. 2015 Nov;10(11):1821-36.
[2] Begolo D, Erben E, Clayton C. Drug target identification using a trypanosome overexpression library. Antimicrob Agents Chemother. 2014 Oct;58(10):6260-4.
[3] Carnec X, Borges-Cardoso V, Reynard S, et al. Targeting n-myristoyltransferases promotes a pan-Mammarenavirus inhibition through the degradation of the Z matrix protein. PLoS Pathog. 2024 Dec 3;20(12):e1012715.
[4] Xiao P, Meng L, Cui X, et al. VP0 Myristoylation Is Essential for Senecavirus A Replication. Pathogens. 2024 Jul 21;13(7):601.
[5] Tan X, He Y, Yu P, et al. The dual role of FSP1 in programmed cell death: resisting ferroptosis in the cell membrane and promoting necroptosis in the nucleus of THP-1 cells. Mol Med. 2024 Jul 15;30(1):102.
[6] Witwit H, Betancourt CA, Cubitt B, et al. Cellular N-Myristoyl Transferases Are Required for Mammarenavirus Multiplication. Viruses. 2024 Aug 26;16(9):1362.
[7] Brand S, Norcross NR, Thompson S, et al. Lead optimization of a pyrazole sulfonamide series of Trypanosoma brucei N-myristoyltransferase inhibitors: identification and evaluation of CNS penetrant compounds as potential treatments for stage 2 human African trypanosomiasis. J Med Chem. 2014 Dec 11;57(23):9855-69.
[8] Beauchamp E, Yap MC, Iyer A, et al. Targeting N-myristoylation for therapy of B-cell lymphomas. Nat Commun. 2020 Oct 22;11(1):5348.
DDD85646是一种有效的布氏锥虫N-肉豆蔻酰转移酶（NMT）抑制剂，其对于布氏锥虫N-肉豆蔻酰转移酶（TbNMT）的半数抑制浓度（IC₅₀）为2nM，对于人源N-肉豆蔻酰转移酶（hNMT）的IC₅₀为4nM[1]。DDD85646可有效阻止锥虫的增殖[2]。DDD85646还具有抑制病毒复制作用 [3-4]。
在体外，DDD85646（10μM）与铁死亡诱导剂Erastin（10μM）共同处理急性单核细胞白血病THP-1细胞36小时，DDD85646通过抑制FSP1在细胞膜上的定位增强了由脂质过氧化、谷胱甘肽耗竭和线粒体收缩为特征的铁死亡敏感性[5]。DDD85646（0.1–10μM）预处理A549、HEK293T、HAP1及Vero E6细胞1–5小时，随后以淋巴脉络丛脑膜炎病毒（LCMV；MOI=0.05–1）感染24–72小时，显著抑制病毒蛋白的表达，同时降低病毒滴度并减少感染细胞数量[6]。
在体内，DDD85646（12.5–50mg/kg）每日两次口服给药，用于处理感染布氏锥虫S427株或STIB900株的小鼠4天，显著清除了外周血中的寄生虫[7]。DDD85646（20–60mg/kg）每日一次或隔日一次皮下注射给药，用于处理携带DOHH2或BL2淋巴瘤异种移植瘤的小鼠7–16天，显著抑制了肿瘤生长并诱导了完全消退[8]。