Rational design, synthesis, evaluation, and crystal structure of a potent inhibitor of human GAR tfase: 10-(trifluoroacetyl)-5,10-dideazaacyclic-5,6,7,8-tetrahydrofolic acid


Zhang, Y., Desharnais, J., Marsilje, T.H., Li, C.L., Hedrick, M.P., Gooljarsingh, L.T., Tavassoli, A., Benkovic, S.J., Olson, A.J., Boger, D.L. and Wilson, I.A. (2003) Rational design, synthesis, evaluation, and crystal structure of a potent inhibitor of human GAR tfase: 10-(trifluoroacetyl)-5,10-dideazaacyclic-5,6,7,8-tetrahydrofolic acid. Biochemistry, 42, (20), 6043-6056. (doi:10.1021/bi034219c).

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Original Publication URL: http://dx.doi.org/10.1021/bi034219c

Description/Abstract

Glycinamide ribonucleotide transformylase (GAR Tfase) has been the target of anti-neoplastic intervention for almost two decades. Here, we use a structure-based approach to design a novel folate analogue, 10-(trifluoroacetyl)-5,10-dideazaacyclic-5,6,7,8-tetrahydrofolic acid (10-CF3CO-DDACTHF, 1), which specifically inhibits recombinant human GAR Tfase (Ki = 15 nM), but is inactive (Ki > 100 μM) against other folate-dependent enzymes that have been examined. Moreover, compound 1 is a potent inhibitor of tumor cell proliferation (IC50 = 16 nM, CCRF-CEM), which represents a 10-fold improvement over Lometrexol, a GAR Tfase inhibitor that has been in clinical trials. Thus, this folate analogue 1 is among the most potent and selective inhibitors known toward GAR Tfase. Contributing to its efficacious activity, compound 1 is effectively transported into the cell by the reduced folate carrier and intracellularly sequestered by polyglutamation. The crystal structure of human GAR Tfase with folate analogue 1 at 1.98 A resolution represents the first structure of any GAR Tfase to be determined with a cofactor or cofactor analogue without the presence of substrate. The folate-binding loop of residues 141-146, which is highly flexible in both Escherichia coli and unliganded human GAR Tfase structures, becomes highly ordered upon binding 1 in the folate-binding site. Computational docking of the natural cofactor into this and other apo or complexed structures provides a rational basis for modeling how the natural cofactor 10-formyltetrahydrofolic acid interacts with GAR Tfase, and suggests that this folate analogue-bound conformation represents the best template to date for inhibitor design.

Item Type: Article
ISSNs: 0006-2960 (print)
Related URLs:
Keywords: functional complementation, biological evaluation,10-trideazafolic acid,glycinamide ribonucleotide transformylase, selective-inhibition, oral, kinetic mechanism, folic-acid, folate-binding-protein, active-site, escherichia-coli,8, 10-formyl-5
Subjects: Q Science
Q Science > QD Chemistry
Divisions: University Structure - Pre August 2011 > School of Chemistry
ePrint ID: 54181
Date Deposited: 31 Jul 2008
Last Modified: 27 Mar 2014 18:37
URI: http://eprints.soton.ac.uk/id/eprint/54181

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