2. Academic Validation
  3. Inhibitors of Mutant Isocitrate Dehydrogenases 1 and 2 (mIDH1/2): An Update and Perspective

Inhibitors of Mutant Isocitrate Dehydrogenases 1 and 2 (mIDH1/2): An Update and Perspective

  • J Med Chem. 2018 Oct 25;61(20):8981-9003. doi: 10.1021/acs.jmedchem.8b00159.
Tianfang Ma 1 2,  Fangxia Zou 1 2,  Stefan Pusch 3 4,  Yungen Xu 2,  Andreas von Deimling 3 4,  Xiaoming Zha 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Engineering and Department of Biochemical Engineering , China Pharmaceutical University , 639 Longmian Avenue , Nanjing 211198 , P. R. China.
  • 2 Department of Medicinal Chemistry , China Pharmaceutical University , 24 Tongjiaxiang , Nanjing 210009 , P. R. China.
  • 3 German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), INF 280, Heidelberg D-69120 , Germany.
  • 4 Department of Neuropathology, Institute of Pathology , Ruprecht-Karls-Universität Heidelberg , INF 224, Heidelberg D-69120 , Germany.
PMID: 29847930 DOI: 10.1021/acs.jmedchem.8b00159
Abstract

Isocitrate dehydrogenases 1 and 2 (IDH1/2) are homodimeric enzymes that catalyze the conversion of isocitrate to α-ketoglutarate (α-KG) in the tricarboxylic acid cycle. However, mutant IDH1/2 (mIDH1/2) reduces α-KG to the oncometabolite 2-hydroxyglutarate (2-HG). High levels of 2-HG competitively inhibit the α-KG-dependent dioxygenases involved in histone and DNA demethylation, thereby impairing normal cellular differentiation and promoting tumor development. Thus, small molecules that inhibit these mutant enzymes may be therapeutically beneficial. Recently, an increasing number of mIDH1/2 inhibitors have been reported. In this review, we summarize the molecular basis of mIDH1/2 and the activity, binding modes, and progress in clinical application of mIDH1/2 inhibitors. We note important future research directions for mIDH1/2 inhibitors and discuss potential therapeutic strategies for the development of mIDH1/2 inhibitors to treat IDH1/2 mutated tumors.

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