|Publication Type||Journal Article|
|Year of Publication||2016|
|Authors||Law, JM, Stark, SC, Liu, K, Liang, NE, Hussain, MM, Leiendecker, M, Ito, D, Verho, O, Stern, AM, Johnston, SE, Zhang, Y-L, Dunn, GP, Shamji, AF, Schreiber, SL|
|Journal||ACS Med Chem Lett|
|Date Published||2016 Oct 13|
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.
|Alternate Journal||ACS Med Chem Lett|
|PubMed Central ID||PMC5066158|