5IZQ

Crystal structure of human folate receptor alpha in complex with novel antifolate AGF183

Summary for 5IZQ

• Entry DOI: 10.2210/pdb5izq/pdb
• Descriptor: Folate receptor alpha, N-(4-{[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)ethyl]amino}benzene-1-carbonyl)-L-glutamic acid (2 entities in total)
• Functional Keywords: folate receptor alpha, antifolate, tumor targeting, 2-amino-4-oxo-6-substituted pyrrolo[2, 3-d]pyrimidine, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 8
• Total formula weight: 224821.16

Authors

Ke, J.,Gu, X.,Brunzelle, J.S.,Xu, H.E.,Melcher, K. (deposition date: 2016-03-25, release date: 2016-08-10, Last modification date: 2024-10-16)

Primary citation

Golani, L.K.,Wallace-Povirk, A.,Deis, S.M.,Wong, J.,Ke, J.,Gu, X.,Raghavan, S.,Wilson, M.R.,Li, X.,Polin, L.,de Waal, P.W.,White, K.,Kushner, J.,O'Connor, C.,Hou, Z.,Xu, H.E.,Melcher, K.,Dann, C.E.,Matherly, L.H.,Gangjee, A.
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.
J.Med.Chem., 59:7856-7876, 2016

PubMed Abstract: Targeted 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) α and β or the proton-coupled folate transporter. Results show increased in vitro antiproliferative activity toward engineered Chinese hamster ovary cells expressing FRs by 4-9 over the CH2 analogue 1. Compounds 4-9 inhibited de novo purine biosynthesis and glycinamide ribonucleotide formyltransferase (GARFTase). X-ray crystal structures for 4 with FRα and GARFTase showed that the bound conformations of 4 required flexibility for attachment to both FRα 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.

PubMed: 27458733
DOI: 10.1021/acs.jmedchem.6b00594

Experimental method

X-RAY DIFFRACTION (3.6 Å)