9ISE

Human MTHFD1 in complex with LY374571

9ISE の概要

• エントリーDOI: 10.2210/pdb9ise/pdb
• 関連するPDBエントリー: 9IS9
• 分子名称: C-1-tetrahydrofolate synthase, cytoplasmic, N-terminally processed, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, (2S)-2-[[4-[[2,4-bis(azanyl)-6-oxidanylidene-1H-pyrimidin-5-yl]carbamoylamino]phenyl]carbonylamino]pentanedioic acid, ... (4 entities in total)
• 機能のキーワード: mthfd1, methylenetetrahydrofolate dehydrogenase/cyclohydrolase, oxidoreductase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 139069.07

構造登録者

Lee, L.C.,Wu, S.Y. (登録日: 2024-07-17, 公開日: 2025-01-01)

主引用文献

Chang, H.H.,Lee, L.C.,Hsu, T.,Peng, Y.H.,Huang, C.H.,Yeh, T.K.,Lu, C.T.,Huang, Z.T.,Hsueh, C.C.,Kung, F.C.,Lin, L.M.,Huang, Y.C.,Wang, Y.H.,Li, L.H.,Tang, Y.C.,Chang, L.,Hsieh, C.C.,Jiaang, W.T.,Kuo, C.C.,Wu, S.Y.
Development of Potent and Selective Inhibitors of Methylenetetrahydrofolate Dehydrogenase 2 for Targeting Acute Myeloid Leukemia: SAR, Structural Insights, and Biological Characterization.
J.Med.Chem., 67:21106-21125, 2024

PubMed Abstract: Methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2 (MTHFD2), a pivotal mitochondrial enzyme in one-carbon metabolism, is significantly upregulated in various cancers but minimally expressed in normal proliferating cells. In contrast, MTHFD1, which performs similar functions, is predominantly expressed in normal cells. Therefore, targeting MTHFD2 with selective inhibitors holds promise for a broader therapeutic window with reduced toxicity and fewer side effects. This study identified selective 2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl ureido-based derivatives through systematic chemical modifications and SAR studies. Structural biology investigations revealed substitutions in the phenyl ring and tail region modulate potency and selectivity toward MTHFD2. Additionally, a comprehensive cell screening platform revealed acute myeloid leukemia cells with FLT3 internal tandem duplication mutations are particularly sensitive to these inhibitors. Furthermore, synergistic effects were observed when combining potential compounds with Alimta. Compound emerged as a leading candidate, demonstrating superior inhibition and selectivity for MTHFD2, favorable pharmacokinetics, and potent antitumor efficacy in MOLM-14 xenograft models.

PubMed: 39591507
DOI: 10.1021/acs.jmedchem.4c01775

実験手法

X-RAY DIFFRACTION (1.99 Å)