Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 7, Issue 10, Pages 944-949Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.6b00264
Keywords
BRD2879; isocitrate dehydrogenase; 2-hydroxyglutarate; glioma; AML; cancer; diversity-oriented synthesis; high-throughput screening; allele-selective probe; small-molecule probe
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Funding
- NCI's Cancer Target Discovery and Development grant [U01CA176152]
- Howard Hughes Medical Institute
- Kekule Fellowship (Fonds der Chemischen Industrie)
- German Academic Exchange Service (DAAD)
- Wenner-Gren Foundations
- Swedish Chemical Society (Stiftelsen Bengt Lundqvists Minne)
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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 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. glioma.
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