biostudies-literatureUnknown10(6)Kawai JMethylenetetrahydrofolate dehydrogenase 2 (MTHFD2) plays a key role in one-carbon (1C) metabolism in human mitochondria, and its high expression correlates with poor survival of patients with various types of cancer. An isozyme-selective MTHFD2 inhibitor is highly attractive for potential use in cancer treatment. Herein, we disclose a novel isozyme-selective MTHFD2 inhibitor DS44960156, with a tricyclic coumarin scaffold, which was initially discovered via high-throughput screening (HTS) and improved using structure-based drug design (SBDD). DS44960156 would offer a good starting point for further optimization based on the following features: (1) unprecedented selectivity (>18-fold) for MTHFD2 over MTHFD1, (2) a molecular weight of less than 400, and (3) good ligand efficiency (LE).ACS medicinal chemistry letters893-898https://www.ebi.ac.uk/biostudies/studies/S-EPMC6580548biostudies-literatureStructure-Based Design and Synthesis of an Isozyme-Selective MTHFD2 Inhibitor with a Tricyclic Coumarin Scaffold.PMC6580548Suzuki MOhki HOta MKawai JShimada TToki TInoue HMatsui SSugihara CTakaishi SMatsui YNakayama KMatsuhashi NfalseStructure-Based Design and Synthesis of an Isozyme-Selective MTHFD2 Inhibitor with a Tricyclic Coumarin Scaffold.Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) plays a key role in one-carbon (1C) metabolism in human mitochondria, and its high expression correlates with poor survival of patients with various types of cancer. An isozyme-selective MTHFD2 inhibitor is highly attractive for potential use in cancer treatment. Herein, we disclose a novel isozyme-selective MTHFD2 inhibitor DS44960156, with a tricyclic coumarin scaffold, which was initially discovered via high-throughput screening (HTS) and improved using structure-based drug design (SBDD). DS44960156 would offer a good starting point for further optimization based on the following features: (1) unprecedented selectivity (>18-fold) for MTHFD2 over MTHFD1, (2) a molecular weight of less than 400, and (3) good ligand efficiency (LE).2019-01-01T00:00:00Z2019 Jun2026-05-01T18:20:03.585Z2020-06-17T07:02:35ZS-EPMC65805483122344410.1021/acsmedchemlett.9b00069