Discovery of AICAR Tfase inhibitors that disrupt requisite enzyme dimerization.
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.
Capps
Kevin J
KJ
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
Humiston
Jon
J
Dominique
Romyr
R
Hwang
Inkyu
I
Boger
Dale L
DL
D019281:Dimerization; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019877:Hydroxymethyl and Formyl Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007700:Kinetics; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase
D004791:Enzyme Inhibitors; D019877:Hydroxymethyl and Formyl Transferases; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase