5izq
From Proteopedia
Crystal structure of human folate receptor alpha in complex with novel antifolate AGF183
Structural highlights
Disease[FOLR1_HUMAN] Neurodegenerative syndrome due to cerebral folate transport deficiency. Neurodegeneration due to cerebral folate transport deficiency (NCFTD) [MIM:613068]: A neurodegenerative disorder resulting from brain-specific folate deficiency early in life. Onset is apparent in late infancy with severe developmental regression, movement disturbances, epilepsy and leukodystrophy. Note=The disease is caused by mutations affecting the gene represented in this entry. Function[FOLR1_HUMAN] Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate to the interior of cells. Publication Abstract from PubMedTargeted antifolates with heteroatom replacements of the carbon vicinal to the phenyl ring in 1 by N (4), O (8), or S (9), or with N-substituted formyl (5), acetyl (6), or trifluoroacetyl (7) moieties, were synthesized and tested for selective cellular uptake by folate receptor (FR) alpha and beta or the proton-coupled folate transporter. Results show increased in vitro anti-proliferative activity toward engineered Chinese hamster ovary cells expressing FRs by 4-9 over the CH2 analog 1. Compounds 4-9 inhibited de novo purine biosynthesis and glycinamide ribonucleotide formyltransferase (GARFTase). X-ray crystal structures for 4 with FRalpha and GARFTase showed that the bound conformations of 4 required flexibility for attachment to both FRalpha and GARFTase. In mice bearing IGROV1 ovarian tumor xenografts, 4 was highly efficacious. Our results establish that heteroatom substitutions in the 3-atom bridge region of 6-substituted pyrrolo[2,3-d]pyrimidines related to 1 provide targeted antifolates that warrant further evaluation as anticancer agents. Tumor Targeting with Novel 6-Substituted Pyrrolo [2,3-d] Pyrimidine Antifolates with Heteroatom Bridge Substitutions Via Cellular Uptake by Folate Receptor alpha and the Proton-coupled Folate Transporter and Inhibition of De Novo Purine Nucleotide Biosynthesis.,Golani LK, Wallace-Povirk A, Deis SM, Wong JE, Ke J, Gu X, Raghavan S, Wilson MR, Li X, Polin LA, de Waal PW, White K, Kushner J, O'Connor CE, Hou Z, Xu HE, Melcher K, Dann Iii CE, Matherly LH, Gangjee A J Med Chem. 2016 Jul 26. PMID:27458733[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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