INSERM UMR_S 999, Hôpital Marie Lannelongue, 92350 Le Plessis-Robinson , France.
Université Paris-Sud et Université Paris-Saclay , 94270 Le Kremlin-Bicêtre , France.
J Med Chem. 2018 Apr 12;61(7):2725-2736. doi: 10.1021/acs.jmedchem.7b01312. Epub 2018 Mar 19.
Macrophage migration inhibitory factor (MIF) is a key pleiotropic mediator and a promising therapeutic target in cancer as well as in several inflammatory and cardiovascular diseases including pulmonary arterial hypertension (PAH). Here, a novel series of N-(phenylmethyl)-benzoxazol-2-thiones 5-32 designed to target the MIF tautomerase active site was synthesized and evaluated for its effects on cell survival. Investigation of structure-activity relationship (SAR) particularly at the 5-position of the benzoxazole core led to the identification of 31 that potently inhibits cell survival in DU-145 prostate cancer cells and pulmonary endothelial cells derived from patients with idiopathic PAH (iPAH-ECs), two cell lines for which survival is MIF-dependent. Molecular docking studies helped to interpret initial SAR related to MIF tautomerase inhibition and propose preferred binding mode for 31 within the MIF tautomerase active site. Interestingly, daily treatment with 31 started 2 weeks after a subcutaneous monocrotaline injection regressed established pulmonary hypertension in rats.
巨噬细胞移动抑制因子（MIF）是癌症以及几种炎症和心血管疾病（包括肺动脉高压（PAH））中的关键多效介质和有前途的治疗靶点。在这里，设计用于靶向 MIF 互变异构酶活性位点的一系列新型 N-(苯基甲基)-苯并恶唑-2-硫代 5-32 被合成并评估其对细胞存活的影响。对构效关系（SAR）的研究，特别是对苯并恶唑核心的 5 位的研究，导致鉴定出 31，其强烈抑制前列腺癌 DU-145 细胞和特发性 PAH（iPAH-ECs）患者来源的肺内皮细胞的存活，这两种细胞系的存活依赖于 MIF。分子对接研究有助于解释与 MIF 互变异构酶抑制相关的初始 SAR，并提出 31 在 MIF 互变异构酶活性位点中的优选结合模式。有趣的是，在皮下注射单克隆毒素后 2 周开始每天用 31 治疗，可使大鼠已建立的肺动脉高压消退。
