The First Structure of Human MTHFD2L and Its Implications for the Development of Isoform-Selective Inhibitors,ChemMedChem

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The First Structure of Human MTHFD2L and Its Implications for the Development of Isoform-Selective Inhibitors
ChemMedChem ( IF 3.6 ) Pub Date : 2022-06-17 , DOI: 10.1002/cmdc.202200274
Emma R Scaletti ₁ , Robert Gustafsson Westergren ₁ , Yasmin Andersson ₂ , Elisee Wiita ₃ , Martin Henriksson ₃ , Evert J Homan ₃ , Ann-Sofie Jemth ₃ , Thomas Helleday _{3,

4} , Pål Stenmark ₁

Affiliation

Pinning down selectivity: MTHFD2 is an anti-cancer drug target only expressed in cancer cells. However, MTHFD2 inhibitors also target MTHFD1 and MTHFD2L, which are expressed in healthy cells. The first structure of human MTHFD2L and its complex with a potent inhibitor reveals the structural basis for inhibition differences between isoforms and highlights the challenges and opportunities in developing selective MTHFD2 inhibitors targeting the folate, cofactor and allosteric binding sites.

中文翻译：

人 MTHFD2L 的第一个结构及其对异构体选择性抑制剂开发的意义

确定选择性：MTHFD2 是一种仅在癌细胞中表达的抗癌药物靶点。然而，MTHFD2 抑制剂还针对在健康细胞中表达的 MTHFD1 和 MTHFD2L。人类 MTHFD2L 及其与有效抑制剂的复合物的第一个结构揭示了异构体之间抑制差异的结构基础，并强调了开发针对叶酸、辅因子和变构结合位点的选择性 MTHFD2 抑制剂的挑战和机遇。

更新日期：2022-06-17

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