选择性且能穿透血脑屏障的羊毛甾醇合酶抑制剂通过诱导 24(S),25-环氧胆固醇的产生来靶向神经胶质瘤干细胞。
Selective and brain-penetrant lanosterol synthase inhibitors target glioma stem-like cells by inducing 24(S),25-epoxycholesterol production.
机构信息
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Children's Medical Center Research Institute and Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
出版信息
Cell Chem Biol. 2023 Feb 16;30(2):214-229.e18. doi: 10.1016/j.chembiol.2023.01.005. Epub 2023 Feb 8.
Abstract
Glioblastoma (GBM) is an aggressive adult brain cancer with few treatment options due in part to the challenges of identifying brain-penetrant drugs. Here, we investigated the mechanism of MM0299, a tetracyclic dicarboximide with anti-glioblastoma activity. MM0299 inhibits lanosterol synthase (LSS) and diverts sterol flux away from cholesterol into a "shunt" pathway that culminates in 24(S),25-epoxycholesterol (EPC). EPC synthesis following MM0299 treatment is both necessary and sufficient to block the growth of mouse and human glioma stem-like cells by depleting cellular cholesterol. MM0299 exhibits superior selectivity for LSS over other sterol biosynthetic enzymes. Critical for its application in the brain, we report an MM0299 derivative that is orally bioavailable, brain-penetrant, and induces the production of EPC in orthotopic GBM tumors but not normal mouse brain. These studies have implications for the development of an LSS inhibitor to treat GBM or other neurologic indications.
摘要
胶质母细胞瘤（GBM）是一种侵袭性成人脑癌，由于难以确定具有脑穿透性的药物，因此治疗选择有限。在这里，我们研究了具有抗胶质母细胞瘤活性的四环二羧酸二酰亚胺 MM0299 的作用机制。MM0299 抑制羊毛甾醇合酶（LSS），并将甾醇通量从胆固醇转移到“分流”途径，最终导致 24(S),25-环氧胆固醇（EPC）的形成。用 MM0299 处理后 EPC 的合成对于通过耗尽细胞胆固醇来阻止小鼠和人神经胶质瘤干细胞的生长是必需且充分的。MM0299 对 LSS 的选择性优于其他甾醇生物合成酶。对其在大脑中的应用至关重要的是，我们报告了一种 MM0299 衍生物，它具有口服生物利用度、脑穿透性，并在原位 GBM 肿瘤中诱导 EPC 的产生，但不会在正常小鼠脑中产生。这些研究对于开发 LSS 抑制剂来治疗 GBM 或其他神经学适应症具有重要意义。
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