title: Targeting tumour proliferation with a small-molecule inhibitor of AICAR transformylase homodimerization.
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.
authors: School of Chemistry, University of Southampton, Southampton, SO17 1BJ, UK.
authors: Ian B
authors: IB
authors: Spurr
authors: Charles N
authors: CN
authors: Birts
authors: Francesco
authors: F
authors: Cuda
authors: Stephen J
authors: SJ
authors: Benkovic
authors: Jeremy P
authors: JP
authors: Blaydes
authors: Ali
authors: A
authors: Tavassoli
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D020134:Catalytic Domain / Q000187:drug effects; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D057166:High-Throughput Screening Assays; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D008970:Molecular Weight; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010456:Peptides, Cyclic; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase