Discovery and development of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives as Bcl-2/Mcl-1 inhibitors.
Bcl-2 family proteins play a vital role for cancer cell in escaping apoptosis, and small-molecule anti-apoptotic Bcl-2 protein inhibitors have been developed as new anticancer therapies. In current study, a series of substituted 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were developed based on the lead compound 1 (Ki = 5.2 µM against Bcl-2 protein). The fluorescence polarization assays suggested that active compounds possessed potent binding affinities to both Bcl-2 and Mcl-1 protein, but had minor or no binding affinities to Bcl-XL protein. MTT assays showed that these compounds had certain anti-proliferative activities against cancer cells. Furthermore, it was found that active compound 11t could induce cell apoptosis and caspase-3 activation in a dose-dependent manner in Jurkat cells.
['Liu|Renshuai|R|', 'Liu|Lulu|L|', 'Yang|Xinying|X|', 'Fang|Hao|H|']
D004305:Dose-Response Relationship, Drug D055808:Drug Discovery D006801:Humans D019169:Jurkat Cells D062105:Molecular Docking Simulation D015394:Molecular Structure D064549:Myeloid Cell Leukemia Sequence 1 Protein D019253:Proto-Oncogene Proteins c-bcl-2 D013329:Structure-Activity Relationship D044005:Tetrahydroisoquinolines
1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid Bcl-2 Apoptosis Anti-tumor