二氢叶酸还原酶
甲氨蝶呤
泛素连接酶
蛋白酶体
蛋白质水解
化学
叶酸受体
DNA连接酶
生物化学
计算生物学
生物
酶
泛素
癌细胞
基因
癌症
免疫学
遗传学
作者
Sandeep Rana,Patricia Dranchak,Jayme L. Dahlin,Laurence Lamy,Wenqing Li,Erin Oliphant,Jonathan H. Shrimp,Girish H. Rajacharya,Ravi Tharakan,David Holland,Apryl S. Whitten,Kelli Wilson,Pankaj K. Singh,Scott K. Durum,Dingyin Tao,Ganesha Rai,James Inglese
标识
DOI:10.1016/j.chembiol.2023.09.014
摘要
Methotrexate (MTX) is a tight-binding dihydrofolate reductase (DHFR) inhibitor, used as both an antineoplastic and immunosuppressant therapeutic. MTX, like folate undergoes folylpolyglutamate synthetase-mediated γ-glutamylation, which affects cellular retention and target specificity. Mechanisms of MTX resistance in cancers include a decrease in MTX poly-γ-glutamylation and an upregulation of DHFR. Here, we report a series of potent MTX-based proteolysis targeting chimeras (PROTACs) to investigate DHFR degradation pharmacology and one-carbon biochemistry. These on-target, cell-active PROTACs show proteasome- and E3 ligase-dependent activity, and selective degradation of DHFR in multiple cancer cell lines. By comparison, treatment with MTX increases cellular DHFR protein expression. Importantly, these PROTACs produced distinct, less-lethal phenotypes compared to MTX. The chemical probe set described here should complement conventional DHFR inhibitors and serve as useful tools for studying one-carbon biochemistry and dissecting complex polypharmacology of MTX and related drugs. Such compounds may also serve as leads for potential autoimmune and antineoplastic therapeutics.
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