Discovery of novel TAOK2 inhibitor scaffolds from high-throughput screening

• Published in: Bioorganic & medicinal chemistry letters Vol. 26; no. 16; pp. 3923 - 3927
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.08.2016
• Subjects: Autophagy; Autophagy - drug effects; Cell Line, Tumor; Drug discovery; Drug Evaluation, Preclinical; High-throughput screening; High-Throughput Screening Assays; Humans; Inhibitor; Kinase; MAP3K; p38 Mitogen-Activated Protein Kinases - chemistry; p38 Mitogen-Activated Protein Kinases - metabolism; Protein Binding; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - toxicity; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Small Molecule Libraries - chemistry; Small Molecule Libraries - metabolism; Small Molecule Libraries - toxicity; Structure-Activity Relationship; Transition Temperature; High-throughput screening; Inhibitor; Drug discovery; Kinase; Autophagy; MAP3K
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.07.016

[Display omitted] 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.