title: Discovery of AICAR Tfase inhibitors that disrupt requisite enzyme dimerization.
abstract: The discovery of a new class of aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase) inhibitors through screening peptidomimetic libraries (>40,000 compounds) that act by inhibiting requisite enzyme dimerization is disclosed. In addition to defining key structural features of the lead compounds responsible for the activity, kinetic analysis of the remarkably small inhibitors established that they act as noncompetitive, dissociative inhibitors of AICAR Tfase with the prototypical lead (A1B3, Cappsin 1) exhibiting a K(i) of 3.1 +/- 0.3 microM. Thus, the studies define a unique approach to selectively targeting AICAR Tfase over all other folate-dependent enzymes, and it represents only one of a few enzymes for which inhibition achieved by disrupting requisite enzyme dimerization has emerged from screening unbiased combinatorial libraries.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Capps
authors.forename: Jon
authors.initials: J
authors.lastname: Humiston
authors.forename: Romyr
authors.initials: R
authors.lastname: Dominique
authors.forename: Inkyu
authors.initials: I
authors.lastname: Hwang
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
mesh_terms: D019281:Dimerization; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019877:Hydroxymethyl and Formyl Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007700:Kinetics; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase
chemical_list: D004791:Enzyme Inhibitors; D019877:Hydroxymethyl and Formyl Transferases; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase