Discovery of novel TAOK2 inhibitor scaffolds from high-throughput screening

作者：Piala Alexander T; Akella Radha; Potts Malia B; Dudics Giagnocavo Stephanie A; He Haixia; Wei Shuguang; White Michael A; Posner Bruce A; Goldsmith Elizabeth J^*

来源：Bioorganic & Medicinal Chemistry Letters, 2016, 26(16): 3923-3927.

DOI：10.1016/j.bmcl.2016.07.016

• Kinase
• MAP3K
• High-throughput screening
• Autophagy
• Drug discovery
• Inhibitor

The MAP3K (Mitogen Activated Protein Kinase Kinase Kinase) TAOK2 (Thousand-And-One Kinase 2) is an activator of p38 MAP kinase cascade that is up-regulated in response to environmental stresses. A synthetic lethal screen performed using a NSCLC (non-small cell lung cancer) cell line, and a second screen identifying potential modulators of autophagy have implicated TAOK2 as a potential cancer therapeutic target. Using a 200,000 compound high throughput screen, we identified three specific small molecule compounds that inhibit the kinase activity of TAOK2. These compounds also showed inhibition of autophagy. Based on SAR (structure-activity relationship) studies, we have predicted the modifications on the reactive groups for the three compounds.

• 出版日期2016-8-15