Somatic mutations in isocitrate dehydrogenases (IDH1/2) have been found in >70%of grade II-III gliomas and secondary glioblastomas, ~15% of acute myeloid leukemias,~56% central and periosteal chondrosarcoma, and less frequently in other tumor types.These cancer-associated mutations lead to a new enzyme activity: the reduction of a-ketoglutarate to (R)-2-hydroxyglutarate and thereby >50-fold higher (R)-2-hydroxyglutarate levels in patient samples. Allele-specific small-molecule probes against mutant or wild-type IDH are needed to illuminate the mutations' role in cancerinitiation, maintenance, and progression. We have discovered an inhibitor of IDH1-R132H, derived from diversity-oriented synthesis and guided by stereochemical structure/activity relationships, capable of modulating mutant IDH1 activity in cells.

Identification of an allele-selective, small-molecule inhibitor of the oncogenic ketoreductase activity of isocitrate dehydrogenase

245th National Meeting (2013)

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