Discovery of wrightiadione as a novel template for the TrkA kinase inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 25; no. 22; pp. 5186 - 5189
• Main Authors: Jeong, Yujeong, Lim, Sang Min, Hong, Sungwoo
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.11.2015; Elsevier
• Subjects: Anticancer; Antineoplastic Agents, Phytogenic - chemistry; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Humans; Indenes - chemistry; Isoflavones - chemistry; Kinase; Life Sciences & Biomedicine; Modeling; Molecular Docking Simulation; Pharmacology & Pharmacy; Physical Sciences; Protein Kinase Inhibitors - chemistry; Quinolines - chemistry; Receptor, trkA - antagonists & inhibitors; Receptor, trkA - chemistry; Science & Technology; Trk inhibitor; Wrightiadione; Trk inhibitor; Anticancer; Kinase; Wrightiadione; Modeling; DESIGN; ANTICANCER AGENTS; COVERAGE; RECEPTOR; IDENTIFICATION; CANCER; POTENT; KINOME; DRUGS; DERIVATIVES
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2015.09.070

[Display omitted] Enzymatic kinase assays and docking simulation studies have shown that the natural product wrightiadione displays inhibitory activity toward TrkA and PLK3. In this study, the template of wrightiadione served as a starting point for Trk inhibitor development campaigns. Molecular simulation provided structural insights for the design of derivatives that were efficiently generated by our recently developed 3-step tandem synthetic approach, resulting in the discovery of compound 2h with biochemical potency at the single-digit micromolar level.