Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases by 2‑Thiohydantoin Compounds

Somatic
mutations of isocitrate dehydrogenase 1 (IDH1) at R132
are frequently found in certain cancers such as glioma. With losing
the activity of wild-type IDH1, the R132H and R132C mutant proteins
can reduce α-ketoglutaric acid (α-KG) to d-2-hydroxyglutaric
acid (D2HG). The resulting high concentration of D2HG inhibits many
α-KG-dependent dioxygenases, including histone demethylases,
to cause broad histone hypermethylation. These aberrant epigenetic
changes are responsible for the initiation of these cancers. We report
the synthesis, structure–activity relationships, enzyme kinetics,
and binding thermodynamics of a novel series of 2-thiohydantoin and
related compounds, among which several compounds are potent inhibitors
of mutant IDH1 with Ki as low as 420 nM.
X-ray crystal structures of IDH1­(R132H) in complex with two inhibitors
are reported, showing their inhibitor–protein interactions.
These compounds can decrease the cellular concentration of D2HG, reduce
the levels of histone methylation, and suppress the proliferation
of stem-like cancer cells in BT142 glioma with IDH1 R132H mutation.