Q3 · MEDICINE
Article
Author: Johnston, Stephen E. ; Zhang, Yan-Ling ; Dunn, Gavin P. ; Shamji, Alykhan F. ; Leiendecker, Matthias ; Verho, Oscar ; Liu, Ke ; Law, Jason M. ; Ito, Daisuke ; Stern, Andrew M. ; Schreiber, Stuart L. ; Stark, Sebastian C. ; Liang, Norah E. ; Hussain, Mahmud M.
Evidence suggests that specific mutations of isocitrate dehydrogenases 1 and 2 (IDH1/2) are critical for the initiation and maintenance of certain tumor types and that inhibiting these mutant enzymes with small molecules may be therapeutically beneficial. In order to discover mutant allele-selective IDH1 inhibitors with chemical features distinct from existing probes, we screened a collection of small molecules derived from diversity-oriented synthesis. The assay identified compounds that inhibit the IDH1-R132H mutant allele commonly found in glioma. Here, we report the discovery of a potent (IC50 = 50 nM) series of IDH1-R132H inhibitors having 8-membered ring sulfonamides as exemplified by the compound BRD2879. The inhibitors suppress (R)-2-hydroxyglutarate production in cells without apparent toxicity. Although the solubility and pharmacokinetic properties of the specific inhibitor BRD2879 prevent its use in vivo, the scaffold presents a validated starting point for the synthesis of future IDH1-R132H inhibitors having improved pharmacological properties.