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Targeting tumour proliferation with a small-molecule inhibitor of AICAR Transformylase Homodimerization

Spurr, Ian B., Birts, Charles N., Cuda, Francesco, Benkovic, Stephen J., Blaydes, Jeremy P. and Tavassoli, Ali (2012) Targeting tumour proliferation with a small-molecule inhibitor of AICAR Transformylase Homodimerization ChemBioChem, 13, (11), pp. 1628-1634. (doi:10.1002/cbic.201200279). (PMID:22764122).

Record type: Article


Aminoimidazole carboxamide ribonucleotide transformylase/ inosine monophosphate cyclohydrolase (ATIC) is a bifunctional homodimeric enzyme that catalyzes the last two steps of de novo purine biosynthesis. Homodimerization of ATIC, a protein-protein interaction with an interface of over 5000 Å(2) , is required for its aminoimidazole carboxamide ribonucleotide (AICAR) transformylase activity, with the active sites forming at the interface of the interacting proteins. Here, we report the development of a small-molecule inhibitor of AICAR transformylase that functions by preventing the homodimerization of ATIC. The compound is derived from a previously reported cyclic hexapeptide inhibitor of AICAR transformylase (with a K(i) of 17 ?M), identified by high-throughput screening. The active motif of the cyclic peptide is identified as an arginine-tyrosine dipeptide, a capped analogue of which inhibits AICAR transformylase with a K(i) value of 84 ?M. A library of nonnatural analogues of this dipeptide was designed, synthesized, and assayed. The most potent compound inhibits AICAR transformylase with a K(i) value of 685 nM, a 25-fold improvement in activity from the parent cyclic peptide. The potential for this AICAR transformylase inhibitor in cancer therapy was assessed by studying its effect on the proliferation of a model breast cancer cell line. Using a nonradioactive proliferation assay and live cell imaging, a dose-dependent reduction in cell numbers and cell division rates was observed in cells treated with our ATIC dimerization inhibitor.

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Published date: 4 July 2012
Keywords: AICAR transformylase, ATIC, cancer, peptides, protein–protein interaction inhibitors
Organisations: Chemistry, Cancer Sciences, Organic Chemistry: SCF


Local EPrints ID: 341205
ISSN: 1439-4227
PURE UUID: 6abcfb52-4705-44bf-bc4e-034268e6c31f
ORCID for Charles N. Birts: ORCID iD
ORCID for Ali Tavassoli: ORCID iD

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Date deposited: 23 Jul 2012 10:59
Last modified: 18 Jul 2017 05:37

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Author: Ian B. Spurr
Author: Francesco Cuda
Author: Stephen J. Benkovic
Author: Ali Tavassoli ORCID iD

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