Summary for 9IT3
| Entry DOI | 10.2210/pdb9it3/pdb |
| Related | 9IS9 9ISC 9ISE 9ISL 9ISR |
| Descriptor | Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial, (2~{S})-2-[[4-[[2,4-bis(azanyl)-6-oxidanylidene-1~{H}-pyrimidin-5-yl]carbamoylamino]-3-chloranyl-phenyl]carbonylamino]pentanedioic acid, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, ... (5 entities in total) |
| Functional Keywords | mthfd2, methylenetetrahydrofolate dehydrogenase 2, 1c metabolism, mitochondria, oxidoreductase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 71646.47 |
| Authors | |
| Primary citation | 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 Cited by 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: 39591507DOI: 10.1021/acs.jmedchem.4c01775 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.06 Å) |
Structure validation
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