Targeting tumour proliferation with a small-molecule inhibitor of AICAR Transformylase Homodimerization
Targeting tumour proliferation with a small-molecule inhibitor of AICAR Transformylase Homodimerization
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.
AICAR transformylase, ATIC, cancer, peptides, protein–protein interaction inhibitors
1628-1634
Spurr, Ian B.
fb87bcbc-46d2-4cb0-8240-ecdfaf013d1d
Birts, Charles N.
8689ddad-ba47-4ca6-82c5-001315dbd250
Cuda, Francesco
8c738a55-70a8-4063-b063-bf83cdf0f270
Benkovic, Stephen J.
f85498a5-27fc-4a22-9069-ff61a4297520
Blaydes, Jeremy P.
e957f999-fd91-4f77-ad62-5b4ef069b15b
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2
4 July 2012
Spurr, Ian B.
fb87bcbc-46d2-4cb0-8240-ecdfaf013d1d
Birts, Charles N.
8689ddad-ba47-4ca6-82c5-001315dbd250
Cuda, Francesco
8c738a55-70a8-4063-b063-bf83cdf0f270
Benkovic, Stephen J.
f85498a5-27fc-4a22-9069-ff61a4297520
Blaydes, Jeremy P.
e957f999-fd91-4f77-ad62-5b4ef069b15b
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2
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), .
(doi:10.1002/cbic.201200279).
(PMID:22764122)
Abstract
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
Identifiers
Local EPrints ID: 341205
URI: http://eprints.soton.ac.uk/id/eprint/341205
ISSN: 1439-4227
PURE UUID: 6abcfb52-4705-44bf-bc4e-034268e6c31f
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Date deposited: 23 Jul 2012 10:59
Last modified: 15 Mar 2024 03:26
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Contributors
Author:
Ian B. Spurr
Author:
Francesco Cuda
Author:
Stephen J. Benkovic
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