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 μM), 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 μM. 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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Authors | Ian B Spurr, Charles N Birts, Francesco Cuda, Stephen J Benkovic, Jeremy P Blaydes, Ali Tavassoli |
Journal | Chembiochem : a European journal of chemical biology
(Chembiochem)
Vol. 13
Issue 11
Pg. 1628-34
(Jul 23 2012)
ISSN: 1439-7633 [Electronic] Germany |
PMID | 22764122
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. |
Chemical References |
- Antineoplastic Agents
- Enzyme Inhibitors
- Peptides, Cyclic
- Phosphoribosylaminoimidazolecarboxamide Formyltransferase
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Topics |
- Antineoplastic Agents
(chemical synthesis, chemistry, pharmacology)
- Breast Neoplasms
(drug therapy, pathology)
- Catalytic Domain
(drug effects)
- Cell Count
- Cell Division
(drug effects)
- Cell Proliferation
(drug effects)
- Dose-Response Relationship, Drug
- Drug Screening Assays, Antitumor
- Enzyme Inhibitors
(chemical synthesis, chemistry, pharmacology)
- Female
- High-Throughput Screening Assays
- Humans
- MCF-7 Cells
- Molecular Structure
- Molecular Weight
- Peptides, Cyclic
(chemical synthesis, chemistry, pharmacology)
- Phosphoribosylaminoimidazolecarboxamide Formyltransferase
(antagonists & inhibitors, chemistry, metabolism)
- Protein Multimerization
(drug effects)
- Structure-Activity Relationship
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