877057-25-5Relevant articles and documents
Structure-guided discovery of selective methionyl-tRNA synthetase inhibitors with potent activity against: Trypanosoma brucei
Buckner, Frederick S.,Choy, Robert K. M.,De Hostos, Eugenio,Faghih, Omeed,Fan, Erkang,Gillespie, J. Robert,Hol, Wim G. J.,Huang, Wenlin,Molasky, Nora M. R.,Mushtaq, Aisha,Ranade, Ranae M.,Shibata, Sayaka,Verlinde, Christophe L. M. J.,Zhang, Zhongsheng,Barros-álvarez, Ximena
, p. 885 - 895 (2020)
Based on crystal structures of Trypanosoma brucei methionyl-tRNA synthetase (TbMetRS) bound to inhibitors, we designed, synthesized, and evaluated two series of novel TbMetRS inhibitors targeting this parasite enzyme. One series has a 1,3-dihydro-imidazol-2-one containing linker, the other has a rigid fused aromatic ring in the linker. For both series of compounds, potent inhibition of parasite growth was achieved with EC50 20?000 nM. Selectivity over human mitochondrial methionyl tRNA synthetase was also evaluated, using a cell-based mitochondrial protein synthesis assay, and selectivity in a range of 20-200-fold was achieved. The inhibitors exhibited poor permeability across the blood brain barrier, necessitating future efforts to optimize the compounds for use in late stage human African trypanosomiasis.
SPECIFIC INHIBITORS OF METHIONYL-TRNA SYNTHETASE
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Paragraph 0403, (2016/03/13)
The present disclosure is generally directed to compositions useful in the inhibition of MetRS and methods for treating diseases that are ameliorated by the inhibition of MetRS.
INHIBITORS OF AKT ACTIVITY
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Page/Page column 54, (2009/04/25)
Invented are novel substituted pyridine compounds, the use of such compounds as inhibitors of protein kinase B activity and in the treatment of cancer and arthritis.
