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Synthesis and biological evaluation of 7H-pyrrolo [2,3-d] pyrimidine derivatives as potential p21-activated kinase 4 (PAK4) inhibitors. 2022

Cong Wang, and Jiawei Xia, and Yan Lei, and Rui Lu, and Mingliang Zhang, and He Lv, and Qianqian Hong, and Tao Lu, and Yadong Chen, and Hongmei Li
Laboratory of Molecular Design and Drug Discovery, China Pharmaceutical University, Nanjing 211198, PR China.

PAK4 has been validated as a crucial effector of various signal pathways and play an important role in driving tumor progression. Here, we developed a series of 7H-pyrrolo [2,3-d] pyrimidine derivatives as PAK4 inhibitors. Compounds 5n and 5o showed higher enzymatic inhibitory activities (IC50 = 2.7 and 20.2 nM, respectively) and potent activity (IC50 = 7.8 and 38.3 nM, respectively) against MV4-11 cell line. Further flow cytometry assay revealed that the compound 5n can arrest MV4-11 cells at G0/G1 phase and induce cell apoptosis. Molecular mechanism study indicated that compound 5n regulated the phosphorylation of PAK4 in vitro. The docking study supported that compound 5n binds to PAK4 through various hydrogen bonding interactions and hydrophobic interactions. Thus, compound 5n represents a promising lead for the discovery of PAK4 directed therapeutic agents and may be considered for further drug development.

UI MeSH Term Description Entries
D011743 Pyrimidines A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (CYTOSINE; THYMINE; and URACIL) and form the basic structure of the barbiturates.
D000970 Antineoplastic Agents Substances that inhibit or prevent the proliferation of NEOPLASMS. Anticancer Agent,Antineoplastic,Antineoplastic Agent,Antineoplastic Drug,Antitumor Agent,Antitumor Drug,Cancer Chemotherapy Agent,Cancer Chemotherapy Drug,Anticancer Agents,Antineoplastic Drugs,Antineoplastics,Antitumor Agents,Antitumor Drugs,Cancer Chemotherapy Agents,Cancer Chemotherapy Drugs,Chemotherapeutic Anticancer Agents,Chemotherapeutic Anticancer Drug,Agent, Anticancer,Agent, Antineoplastic,Agent, Antitumor,Agent, Cancer Chemotherapy,Agents, Anticancer,Agents, Antineoplastic,Agents, Antitumor,Agents, Cancer Chemotherapy,Agents, Chemotherapeutic Anticancer,Chemotherapy Agent, Cancer,Chemotherapy Agents, Cancer,Chemotherapy Drug, Cancer,Chemotherapy Drugs, Cancer,Drug, Antineoplastic,Drug, Antitumor,Drug, Cancer Chemotherapy,Drug, Chemotherapeutic Anticancer,Drugs, Antineoplastic,Drugs, Antitumor,Drugs, Cancer Chemotherapy
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D045744 Cell Line, Tumor A cell line derived from cultured tumor cells. Tumor Cell Line,Cell Lines, Tumor,Line, Tumor Cell,Lines, Tumor Cell,Tumor Cell Lines
D047428 Protein Kinase Inhibitors Agents that inhibit PROTEIN KINASES. Protein Kinase Inhibitor,Inhibitor, Protein Kinase,Inhibitors, Protein Kinase,Kinase Inhibitor, Protein,Kinase Inhibitors, Protein
D049109 Cell Proliferation All of the processes involved in increasing CELL NUMBER including CELL DIVISION. Cell Growth in Number,Cellular Proliferation,Cell Multiplication,Cell Number Growth,Growth, Cell Number,Multiplication, Cell,Number Growth, Cell,Proliferation, Cell,Proliferation, Cellular
D054462 p21-Activated Kinases A family of serine-threonine kinases that bind to and are activated by MONOMERIC GTP-BINDING PROTEINS such as RAC GTP-BINDING PROTEINS and CDC42 GTP-BINDING PROTEIN. They are intracellular signaling kinases that play a role the regulation of cytoskeletal organization. PAK Kinase,p21-Activated Kinase,Oligophrenin-3,PAK Kinases,PAK-1 Kinase,PAK-2 Kinase,PAK1 Kinase,PAK2 Kinase,PAK3 Kinase,PAK65,Serine-Threonine-Protein Kinase PAK 1,Serine-Threonine-Protein Kinase PAK 3,alpha p21-Activated Kinase,alpha-PAK,beta p21-Activated Kinase,beta-PAK,gamma-PAK,p21-Activated Kinase 1,p21-Activated Kinase 2,p21-Activated Kinase 3,p65(PAK),p65PAK Protein,Kinase, PAK,Kinase, p21-Activated,Kinases, PAK,Kinases, p21-Activated,Oligophrenin 3,PAK 1 Kinase,PAK 2 Kinase,Serine Threonine Protein Kinase PAK 1,Serine Threonine Protein Kinase PAK 3,alpha p21 Activated Kinase,beta p21 Activated Kinase,gamma PAK,p21 Activated Kinase,p21 Activated Kinase 1,p21 Activated Kinase 2,p21 Activated Kinase 3,p21 Activated Kinases,p21-Activated Kinase, beta
D062105 Molecular Docking Simulation A computer simulation technique that is used to model the interaction between two molecules. Typically the docking simulation measures the interactions of a small molecule or ligand with a part of a larger molecule such as a protein. Molecular Docking,Molecular Docking Simulations,Molecular Docking Analysis,Analysis, Molecular Docking,Docking Analysis, Molecular,Docking Simulation, Molecular,Docking, Molecular,Molecular Docking Analyses,Molecular Dockings,Simulation, Molecular Docking

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