Discovery of 8-Membered Ring Sulfonamides as Inhibitors of Oncogenic Mutant Isocitrate Dehydrogenase 1

Jason M. Law, Sebastian C. Stark, Ke Liu, Norah E. Liang, Mahmud M. Hussain, Matthias Leiendecker, Daisuke Ito, Oscar Verho, Andrew M. Stern, Stephen E. Johnston, Yan Ling Zhang, Gavin P. Dunn, Alykhan F. Shamji, Stuart L. Schreiber

Research output: Contribution to journalArticle

12 Scopus citations

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 use in vivo, the scaffold presents a validated starting point for the synthesis of future IDH1-R132H inhibitors having improved pharmacological properties.

Original languageEnglish
Pages (from-to)944-949
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume7
Issue number10
DOIs
StatePublished - Oct 13 2016

Keywords

  • 2-hydroxyglutarate
  • AML
  • BRD2879
  • allele-selective probe
  • cancer
  • diversity-oriented synthesis
  • glioma
  • high-throughput screening
  • isocitrate dehydrogenase
  • small-molecule probe

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    Law, J. M., Stark, S. C., Liu, K., Liang, N. E., Hussain, M. M., Leiendecker, M., Ito, D., Verho, O., Stern, A. M., Johnston, S. E., Zhang, Y. L., Dunn, G. P., Shamji, A. F., & Schreiber, S. L. (2016). Discovery of 8-Membered Ring Sulfonamides as Inhibitors of Oncogenic Mutant Isocitrate Dehydrogenase 1. ACS Medicinal Chemistry Letters, 7(10), 944-949. https://doi.org/10.1021/acsmedchemlett.6b00264