Inhibition of cancer-associated mutant isocitrate dehydrogenases: synthesis, structure-activity relationship, and...

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Oncology

Background:

• Mutations in isocitrate dehydrogenase 1 (IDH1) are oncogenic drivers in various cancers, notably glioma.
• Mutant IDH1 enzymes produce oncometabolite D-2-hydroxyglutaric acid (D2HG), promoting cancer initiation.

Purpose of the Study:

• To identify and synthesize novel inhibitors targeting the IDH1(R132H) mutation.
• To investigate the structure-activity relationships (SAR) of 1-hydroxypyridin-2-one derivatives as IDH1 inhibitors.
• To evaluate the selectivity and cellular efficacy of these inhibitors against glioma cells.

Main Methods:

• Synthesis of 61 derivatives based on the 1-hydroxypyridin-2-one scaffold.
• Enzyme inhibition assays to determine inhibitory constants (Ki) against IDH1(R132H) and wild-type (WT) IDH1.
• Cell-based assays to assess D2HG production, blood-brain barrier permeability, and anti-glioma activity (EC50).

Main Results:

• Several 1-hydroxypyridin-2-one derivatives demonstrated potent inhibition of IDH1(R132H) with Ki values as low as 140 nM.
• Inhibitors exhibited high selectivity, with weak or no activity against WT IDH1.
• Compound activity against IDH1(R132C) correlated well with IDH1(R132H) inhibition and D2HG reduction.
• Selected compounds showed blood-brain barrier permeability and potent, selective anti-glioma activity (EC50 = 0.26-1.8 μM) in R132H-mutated cells.

Conclusions:

• 1-hydroxypyridin-2-one derivatives represent a promising class of selective IDH1(R132H) inhibitors.
• These compounds effectively target a key oncogenic pathway in IDH1-mutated gliomas.
• The identified inhibitors possess favorable properties for potential therapeutic development against IDH1-mutated gliomas.