6JIB

Human MTHFD2 in complex with DS44960156

Summary for 6JIB

• Entry DOI: 10.2210/pdb6jib/pdb
• Descriptor: Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial, 4-(5-oxo-1,5-dihydro-2H-[1]benzopyrano[3,4-c]pyridine-3(4H)-carbonyl)benzoic acid, PHOSPHATE ION, ... (5 entities in total)
• Functional Keywords: inhibitor, folate, cofactor, dehydrogenase, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 72478.70

Authors

Suzuki, M.,Matsui, Y.,Kawai, J. (deposition date: 2019-02-20, release date: 2019-06-05, Last modification date: 2023-11-22)

Primary citation

Kawai, J.,Ota, M.,Ohki, H.,Toki, T.,Suzuki, M.,Shimada, T.,Matsui, S.,Inoue, H.,Sugihara, C.,Matsuhashi, N.,Matsui, Y.,Takaishi, S.,Nakayama, K.
Structure-Based Design and Synthesis of an Isozyme-Selective MTHFD2 Inhibitor with a Tricyclic Coumarin Scaffold.
Acs Med.Chem.Lett., 10:893-898, 2019

PubMed Abstract: 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).

PubMed: 31223444
DOI: 10.1021/acsmedchemlett.9b00069

Experimental method

X-RAY DIFFRACTION (2.25 Å)