4-Quinolone-3-carboxylic acids as cell-permeable inhibitors of protein tyrosine phosphatase 1B |
| |
| Institution: | 1. CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China;2. The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guoshoujin Road, Shanghai 201203, China;3. School of Chemical Science and Technology, Yunnan University, Kunming 650091, China;1. Department of Chemistry, College of Science, Engineering and Technology, University of South Africa, Private Bag X06, Florida 1710, South Africa;2. Department of Life & Consumer Sciences, College of Agriculture and Environmental Sciences, University of South Africa, Private Bag X06, Florida 1710, South Africa;1. Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States;2. Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States;3. Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States;4. Materials Chemistry and Crystallography, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States;1. State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, Songhu Road 2005, Shanghai, 200438, China;2. Department of Chemistry, Tongji University, Siping Road 1239, Shanghai, 200092, China;1. Department of Chemistry and Drug Innovation, Vertex Pharmaceuticals, 11010 Torreyana Road, San Diego, CA 92121, United States;2. Department of Drug Metabolism and Pharmacokinetics, Vertex Pharmaceuticals, 11010 Torreyana Road, San Diego, CA 92121, United States;3. Department of Biology, Vertex Pharmaceuticals, 11010 Torreyana Road, San Diego, CA 92121, United States;4. Department of Chemistry, Vertex Pharmaceuticals (Europe) Ltd, 86-88 Jubilee Avenue, Milton Park, Abingdon, Oxfordshire OX14 4RW, United Kingdom;5. Department of Medicinal Chemistry, Vertex Pharmaceuticals, 50 Northern Avenue, Boston, MA 02210, United States;1. Department of Pharmaceutical Engineering, Xihua University, Chengdu 610039, PR China;2. Department of Chemistry, Xihua University, Chengdu 610039, PR China |
| |
| Abstract: | Protein tyrosine phosphatase 1B is a negative regulator in the insulin and leptin signaling pathways, and has emerged as an attractive target for the treatment of type 2 diabetes and obesity. However, the essential pharmacophore of charged phosphotyrosine or its mimetic confer low selectivity and poor cell permeability. Starting from our previously reported aryl diketoacid-based PTP1B inhibitors, a drug-like scaffold of 4-quinolone-3-carboxylic acid was introduced for the first time as a novel surrogate of phosphotyrosine. An optimal combination of hydrophobic groups installed at C-6, N-1 and C-3 positions of the quinolone motif afforded potent PTP1B inhibitors with low micromolar IC50 values. These 4-quinolone-3-carboxylate based PTP1B inhibitors displayed a 2–10 fold selectivity over a panel of PTP’s. Furthermore, the bidentate inhibitors of 4-quinolone-3-carboxylic acids conjugated with aryl diketoacid or salicylic acid were cell permeable and enhanced insulin signaling in CHO/hIR cells. The kinetic studies and molecular modeling suggest that the 4-quinolone-3-carboxylates act as competitive inhibitors by binding to the PTP1B active site in the WPD loop closed conformation. Taken together, our study shows that the 4-quinolone-3-carboxylic acid derivatives exhibit improved pharmacological properties over previously described PTB1B inhibitors and warrant further preclinical studies. |
| |
| Keywords: | Protein tyrosine phosphatase 1B inhibitor 4-Quinolone-3-carboxylic acid Bidentate ligand Bioisostere Insulin receptor signaling |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
