title: Discovery of 8-Membered Ring Sulfonamides as Inhibitors of Oncogenic Mutant Isocitrate Dehydrogenase 1.
abstract: 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 usein vivo, the scaffold presents a validated starting point for the synthesis of future IDH1-R132H inhibitors having improved pharmacological properties.
authors: Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts 02142, United States; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States.
authors: Jason M
authors: JM
authors: Law
authors: Center for the Science of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.
authors: Sebastian C
authors: SC
authors: Stark
authors: Center for the Science of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.
authors: Ke
authors: K
authors: Liu
authors: Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts 02142, United States; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States.
authors: Norah E
authors: NE
authors: Liang
authors: Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts 02142, United States; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States; Howard Hughes Medical Institute, Cambridge, Massachusetts 02138, United States.
authors: Mahmud M
authors: MM
authors: Hussain
authors: Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts 02142, United States; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States.
authors: Matthias
authors: M
authors: Leiendecker
authors: Center for the Science of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.
authors: Daisuke
authors: D
authors: Ito
authors: Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts 02142, United States; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States.
authors: Oscar
authors: O
authors: Verho
authors: Center for the Science of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.
authors: Andrew M
authors: AM
authors: Stern
authors: Center for the Science of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.
authors: Stephen E
authors: SE
authors: Johnston
authors: Center for the Science of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.
authors: Yan-Ling
authors: YL
authors: Zhang
authors: Department of Neurological Surgery, Washington Univeristy School of Medicine , St. Louis, Missouri 63110, United States.
authors: Gavin P
authors: GP
authors: Dunn
authors: Center for the Science of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.
authors: Alykhan F
authors: AF
authors: Shamji
authors: Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts 02142, United States; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States; Howard Hughes Medical Institute, Cambridge, Massachusetts 02138, United States.
authors: Stuart L
authors: SL
authors: Schreiber
keywords: 2-hydroxyglutarate; AML; BRD2879; allele-selective probe; cancer; diversity-oriented synthesis; glioma; high-throughput screening; isocitrate dehydrogenase; small-molecule probe