The discovery of carboline analogs as potent MAPKAP-K2 inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 17; no. 16; pp. 4664 - 4669
• Main Authors: Wu, Jiang-Ping, Wang, Ji, Abeywardane, Asitha, Andersen, Denise, Emmanuel, Michel, Gautschi, Elda, Goldberg, Daniel R., Kashem, Mohammed A., Lukas, Susan, Mao, Wang, Martin, Leslie, Morwick, Tina, Moss, Neil, Pargellis, Christopher, Patel, Usha R., Patnaude, Lori, Peet, Gregory W., Skow, Donna, Snow, Roger J., Ward, Yancey, Werneburg, Brian, White, Andre
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.08.2007; Elsevier
• Subjects: Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Carboline; Carbolines - chemistry; Carbolines - pharmacology; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; MAPKAP-K2; Medical sciences; MK2; MK2a; Models, Molecular; Molecular Structure; Pharmacology. Drug treatments; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Structure-Activity Relationship; MK2a; MK2; MAPKAP-K2; Carboline; Human; Enzyme; Transferases; Thiazole derivatives; Leukemia; Cytokine; Lactam; Enzyme inhibitor; Mitogen-activated protein kinase; Inhibitor enzyme complex; In vitro; Immunological method; Carboline derivatives; Cell line; Structure activity relation; Immunofluorescence; Tumor cell; Crystalline structure
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.05.101

The discovery of a series of potent, carboline-based MK2 inhibitors is described. These compounds inhibit MK2 with IC50s as low as 10nM, as measured in a DELFIA assay. An X-ray crystal structure reveals that they bind in a region near the p-loop and the hinge region of MK2a.