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Your search keyword '"Junyu Xu"' showing total 5 results
Start Over Author "Junyu Xu" Journal journal of medicinal chemistry
5 results on '"Junyu Xu"'

1. Discovery of N-(4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)-4-(4-methylpiperazin-1-yl)quinazolin-7-amine as a Novel, Potent, and Oral Cyclin-Dependent Kinase Inhibitor against Haematological Malignancies

Author

Xiaoyue Liu, Tao Lu, Yadong Chen, Yanmin Zhang, Hongmei Li, Chenhe Liu, Xinren Wang, Tianyi Zhang, Ruinan Dong, Weifang Tang, Jianhang Huang, Shaohua Hou, and Junyu Xu

Subjects
biology, Kinase, Chemistry, Poly ADP ribose polymerase, Caspase 3, Cell cycle, Immune system, Apoptosis, Cyclin-dependent kinase, Drug Discovery, Toxicity, Cancer research, biology.protein, Molecular Medicine
Abstract

Hematologic malignancies (HM) start in blood forming tissue or in the cells of the immune system. Cyclin-dependent kinases (CDKs) regulate cell cycle progression, and some of them control cellular transcription. CDK inhibition can trigger apoptosis and could be particularly useful in hematological malignancies. Herein, we describe our efforts toward the discovery of a novel series of quinazoline derivatives as CDK inhibitors. Intensive structural modifications lead to the identification of compound 37d as the most active inhibitors of CDKs 1, 2, 4, 8 and 9 with balancing potency and selectivity against CDKs. Further biological studies revealed that compound 37d can arrest the cell cycle and induce apoptosis via activating PARP and caspase 3. More importantly, compound 37d showed good antitumor efficacy in multiple HM mice xenograft models with no obvious toxicity. These results indicated that CDK 1, 2, 4, 8, and 9 inhibitors could be potentially used to treat certain hematologic malignancies.

Published
2021

2. Identification of N-Phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine Derivatives as Novel, Potent, and Selective NF-κB Inducing Kinase (NIK) Inhibitors for the Treatment of Psoriasis

Author

You Zhong, Qianqian Gao, Yuqin Zhu, Yanmin Zhang, Bo Kong, Junyu Xu, Haichun Liu, Jianing Song, Fei Jiang, Shuwen Li, Hua Wang, Yuxiang Ma, Hongmei Li, Tao Lu, Yadong Chen, Weidong Zu, Xinren Wang, and Chenhe Liu

Subjects
0303 health sciences, Chemistry, Stereochemistry, Kinase, medicine.disease, 01 natural sciences, Chemical synthesis, Nf κb inducing kinase, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, 03 medical and health sciences, Psoriasis, Drug Discovery, medicine, Molecular Medicine, 030304 developmental biology, Amine derivatives
Abstract

A series of N-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives with NF-κB inducing kinase (NIK) inhibitory activity were obtained through structure-based drug design and synthetic chemistry. A...

Published
2020

3. Discovery of Benzo[cd]indol-2(1H)-ones and Pyrrolo[4,3,2-de]quinolin-2(1H)-ones as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the First Bromodomain with Potential High Efficiency against Acute Gouty Arthritis

Author

Fei Jiang, Qinghua Hu, Zhimin Zhang, Hongmei Li, Huili Li, Dewei Zhang, Hanwen Li, Yu Ma, Jingjing Xu, Haifang Chen, Yong Cui, Yanle Zhi, Yanmin Zhang, Junyu Xu, Jiapeng Zhu, Tao Lu, and Yadong Chen

Subjects
0303 health sciences, BRD4, Drug discovery, Cell growth, Chemistry, Lysine, Arthritis, medicine.disease, 01 natural sciences, 0104 chemical sciences, Bromodomain, 010404 medicinal & biomolecular chemistry, 03 medical and health sciences, Biochemistry, Drug Discovery, medicine, Molecular Medicine, Acute gouty arthritis, Selectivity, 030304 developmental biology
Abstract

The bromodomain and extra-terminal domain (BET) family of proteins are readers which specifically recognize histone-acetylated lysine residues. Each BET bromodomain protein contains two highly homologous domains: the first bromodomain (BD1) and the second bromodomain (BD2). Pan-BET bromodomain inhibition is a potential therapy for various cancers and immune-inflammatory diseases, but only few reported inhibitors show selectivity within the BET family. Herein, we identified a series of benzo[cd]indol-2(1H)-ones and pyrrolo[4,3,2-de]quinolin-2(1H)-ones with good selectivity for BET BD1. Through structure-based optimization, highly active and selective compounds are ultimately obtained. The representative compounds are the first reported inhibitors with selectivity more than 100-fold for BRD4(1) over BRD4(2). Among them, we further show that 68 (LT052) mediates BRD4/NF-κB/NLRP3 signaling inflammatory pathways with comparable protein expression and significantly improves symptoms of gout arthritis in a rat model. Therefore, selective pharmacological modulation of individual bromodomains could represent a strategy for the treatment of acute gouty arthritis.

Published
2019

4. Discovery of

Author

Jianhang, Huang, Xinren, Wang, Ruinan, Dong, Xiaoyue, Liu, Hongmei, Li, Tianyi, Zhang, Junyu, Xu, Chenhe, Liu, Yanmin, Zhang, Shaohua, Hou, Weifang, Tang, Tao, Lu, and Yadong, Chen

Subjects
Molecular Structure, Administration, Oral, Antineoplastic Agents, Cyclin-Dependent Kinase 9, Xenograft Model Antitumor Assays, Mice, Structure-Activity Relationship, Area Under Curve, Catalytic Domain, Cell Line, Tumor, Animals, Humans, Protein Kinase Inhibitors, Half-Life, Protein Binding
Abstract

Hematologic malignancies (HM) start in blood forming tissue or in the cells of the immune system. Cyclin-dependent kinases (CDKs) regulate cell cycle progression, and some of them control cellular transcription. CDK inhibition can trigger apoptosis and could be particularly useful in hematological malignancies. Herein, we describe our efforts toward the discovery of a novel series of quinazoline derivatives as CDK inhibitors. Intensive structural modifications lead to the identification of compound

Published
2021

5. Discovery of Benzo[

Author

Fei, Jiang, Qinghua, Hu, Zhimin, Zhang, Hongmei, Li, Huili, Li, Dewei, Zhang, Hanwen, Li, Yu, Ma, Jingjing, Xu, Haifang, Chen, Yong, Cui, Yanle, Zhi, Yanmin, Zhang, Junyu, Xu, Jiapeng, Zhu, Tao, Lu, and Yadong, Chen

Subjects
Male, Models, Molecular, Sulfonamides, Arthritis, Gouty, Macrophages, Anti-Inflammatory Agents, NF-kappa B, Nuclear Proteins, Crystallography, X-Ray, Arthritis, Experimental, Rats, Rats, Sprague-Dawley, Mice, Antirheumatic Agents, Acute Disease, Drug Discovery, NLR Family, Pyrin Domain-Containing 3 Protein, Human Umbilical Vein Endothelial Cells, Animals, Humans, Cell Proliferation, Transcription Factors
Abstract

The bromodomain and extra-terminal domain (BET) family of proteins are readers which specifically recognize histone-acetylated lysine residues. Each BET bromodomain protein contains two highly homologous domains: the first bromodomain (BD1) and the second bromodomain (BD2). Pan-BET bromodomain inhibition is a potential therapy for various cancers and immune-inflammatory diseases, but only few reported inhibitors show selectivity within the BET family. Herein, we identified a series of benzo[

Published
2019

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