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Your search keyword '"Yan, Yaoyao"' showing total 4 results
Start Over Author "Yan, Yaoyao" Publisher american chemical society
4 results on '"Yan, Yaoyao"'

3. Discovery and In Vivo Anti-inflammatory Activity Evaluation of a Novel Non-peptidyl Non-covalent Cathepsin C Inhibitor.

Author

Chen X, Yan Y, Zhang Z, Zhang F, Liu M, Du L, Zhang H, Shen X, Zhao D, Shi JB, and Liu X

Subjects
Animals, Anti-Inflammatory Agents chemical synthesis, Anti-Inflammatory Agents metabolism, Anti-Inflammatory Agents toxicity, Cathepsin C metabolism, Cell Line, Tumor, Drug Discovery, Humans, Inflammation etiology, Inflammation pathology, Lung drug effects, Lung pathology, Male, Mice, Inbred ICR, Microsomes, Liver metabolism, Molecular Docking Simulation, Molecular Structure, Protease Inhibitors chemical synthesis, Protease Inhibitors metabolism, Protease Inhibitors toxicity, Protein Binding, Pulmonary Disease, Chronic Obstructive complications, Pulmonary Disease, Chronic Obstructive pathology, Pyrimidines chemical synthesis, Pyrimidines metabolism, Pyrimidines toxicity, Rats, Sprague-Dawley, Structure-Activity Relationship, Mice, Rats, Anti-Inflammatory Agents therapeutic use, Cathepsin C antagonists & inhibitors, Inflammation drug therapy, Protease Inhibitors therapeutic use, Pulmonary Disease, Chronic Obstructive drug therapy, Pyrimidines therapeutic use
Abstract

Cathepsin C (Cat C) participates in inflammation and immune regulation by affecting the activation of neutrophil serine proteases (NSPs). Therefore, cathepsin C is an attractive target for treatment of NSP-related inflammatory diseases. Here, the complete discovery process of the first potent "non-peptidyl non-covalent cathepsin C inhibitor" was described with hit finding, structure optimization, and lead discovery. Starting with hit 14 , structure-based optimization and structure-activity relationship study were comprehensively carried out, and lead compound 54 was discovered as a potent drug-like cathepsin C inhibitor both in vivo and in vitro . Also, compound 54 (with cathepsin C Enz IC 50 = 57.4 nM) exhibited effective anti-inflammatory activity in an animal model of chronic obstructive pulmonary disease. These results confirmed that the non-peptidyl and non-covalent derivative could be used as an effective cathepsin C inhibitor and encouraged us to continue further drug discovery on the basis of this finding.

Published
2021
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4. Discovery and SARs of 5-Chloro- N 4 -phenyl- N 2 -(pyridin-2-yl)pyrimidine-2,4-diamine Derivatives as Oral Available and Dual CDK 6 and 9 Inhibitors with Potent Antitumor Activity.

Author

Wang Y, Chen X, Yan Y, Zhu X, Liu M, and Liu X

Subjects
Administration, Oral, Animals, Antineoplastic Agents administration & dosage, Antineoplastic Agents chemical synthesis, Antineoplastic Agents metabolism, Apoptosis drug effects, Catalytic Domain, Cell Line, Tumor, Cell Proliferation drug effects, Cyclin-Dependent Kinase 6 antagonists & inhibitors, Cyclin-Dependent Kinase 6 chemistry, Cyclin-Dependent Kinase 6 metabolism, Cyclin-Dependent Kinase 9 antagonists & inhibitors, Cyclin-Dependent Kinase 9 chemistry, Cyclin-Dependent Kinase 9 metabolism, Humans, Male, Mice, Inbred BALB C, Molecular Docking Simulation, Molecular Structure, Protein Binding, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors metabolism, Pyridines administration & dosage, Pyridines chemical synthesis, Pyridines metabolism, Pyrimidines administration & dosage, Pyrimidines chemical synthesis, Pyrimidines metabolism, Rats, Sprague-Dawley, Structure-Activity Relationship, Antineoplastic Agents therapeutic use, Neoplasms drug therapy, Protein Kinase Inhibitors therapeutic use, Pyridines therapeutic use, Pyrimidines therapeutic use
Abstract

Cyclin-dependent kinases (CDKs) are promising therapeutic targets for cancer therapy. Herein, we describe our efforts toward the discovery of a series of 5-chloro- N 4 -phenyl- N 2 -(pyridin-2-yl)pyrimidine-2,4-diamine derivatives as dual CDK6 and 9 inhibitors. Intensive structural modifications lead to the identification of compound 66 as the most active dual CDK6/9 inhibitor with balancing potency against these two targets and good selectivity over CDK2. Further biological studies revealed that compound 66 was directly bound to CDK6/9, resulting in suppression of their downstream signaling pathway and inhibition of cell proliferation by blocking cell cycle progression and inducing cellular apoptosis. More importantly, compound 66 significantly inhibited tumor growth in a xenograft mouse model with no obvious toxicity, indicating the promising therapeutic potential of CDK6/9 dual inhibitors for cancer treatment. Therefore, the above results are of great importance in the development of dual CDK6/9 inhibitors for cancer therapy.

Published
2020
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