title: Discovery of novel TAOK2 inhibitor scaffolds from high-throughput screening.
abstract: 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.
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8816, United States.
authors.forename: Alexander T
authors.initials: AT
authors.lastname: Piala
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8816, United States.
authors.forename: Radha
authors.initials: R
authors.lastname: Akella
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8816, United States.
authors.forename: Malia B
authors.initials: MB
authors.lastname: Potts
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8816, United States.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Dudics-Giagnocavo
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8816, United States.
authors.forename: Haixia
authors.initials: H
authors.lastname: He
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8816, United States.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Wei
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8816, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: White
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8816, United States.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Posner
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8816, United States. Electronic address: elizabeth.goldsmith@utsouthwestern.edu.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Goldsmith
mesh_terms: D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D006801:Humans; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D013329:Structure-Activity Relationship; D044366:Transition Temperature; D048051:p38 Mitogen-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Autophagy; Drug discovery; High-throughput screening; Inhibitor; Kinase; MAP3K