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Structure-based design, synthesis and bioactivity evaluation of macrocyclic inhibitors of mutant isocitrate dehydrogenase 2 (IDH2) displaying activity in acute myeloid leukemia cells.
- Source :
-
European Journal of Medicinal Chemistry . Oct2020, Vol. 203, pN.PAG-N.PAG. 1p. - Publication Year :
- 2020
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Abstract
- The enzymes involved in the metabolic pathways in cancer cells have been demonstrated as important therapeutic targets such as the isocitrate dehydrogenase 2 (IDH2). A series of macrocyclic derivatives was designed based on the marketed IDH2 inhibitor AG-221 by using the conformational restriction strategy. The resulted compounds showed moderate to good inhibitory potential against different IDH2-mutant enzymes. Amongst, compound C6 exhibited better IDH2R140Q inhibitory potency than AG-221 , and showed excellent activity of 2-hydroxyglutarate (2-HG) suppression in vitro and its mesylate displayed good pharmacokinetic profiles. Moreover, C6 performed strong binding mode to IDH2R140Q after computational docking and dynamic simulation, which may serve as a good starting point for further development. Image 1 • A series of macrocyclic inhibitors targeting mutant IDH2 was designed by using the conformational restriction strategy. • Compound C6 exhibited better IDH2R140Q inhibitory potency than AG-221. • Compound C6 performed strong binding mode to IDHR140Q after computational docking and dynamic simulation. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 02235234
- Volume :
- 203
- Database :
- Academic Search Index
- Journal :
- European Journal of Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 145680829
- Full Text :
- https://doi.org/10.1016/j.ejmech.2020.112491