Discovery of novel TAOK2 inhibitor scaffolds from high-throughput screening

被引：9

作者：

Piala, Alexander T. ^{[1
]}

Akella, Radha ^{[1
]}

Potts, Malia B. ^{[2
]}

Dudics-Giagnocavo, Stephanie A. ^{[2
]}

He, Haixia ^{[1
]}

Wei, Shuguang ^{[3
]}

White, Michael A. ^{[2
]}

Posner, Bruce A. ^{[3
]}

Goldsmith, Elizabeth J. ^{[1
]}

机构：

[1] Univ Texas Southwestern Med Ctr Dallas, Dept Biophys, 5323 Harry Hines Blvd, Dallas, TX 75390 USA

[2] Univ Texas Southwestern Med Ctr Dallas, Dept Cell Biol, 5323 Harry Hines Blvd, Dallas, TX 75390 USA

[3] Univ Texas Southwestern Med Ctr Dallas, Dept Biochem, 5323 Harry Hines Blvd, Dallas, TX 75390 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2016年 / 26卷 / 16期

关键词：

Kinase; MAP3K; High-throughput screening; Autophagy; Drug discovery; Inhibitor; KINASE; IDENTIFICATION; AUTOPHAGY;

D O I：

10.1016/j.bmcl.2016.07.016

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：3923 / 3927

页数：5

共 15 条

[1] The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data [J].

Cerami, Ethan ;

Gao, Jianjiong ;

Dogrusoz, Ugur ;

Gross, Benjamin E. ;

Sumer, Selcuk Onur ;

Aksoy, Buelent Arman ;

Jacobsen, Anders ;

Byrne, Caitlin J. ;

Heuer, Michael L. ;

Larsson, Erik ;

Antipin, Yevgeniy ;

Reva, Boris ;

Goldberg, Arthur P. ;

Sander, Chris ;

Schultz, Nikolaus .

CANCER DISCOVERY, 2012, 2 (05) :401-404

[2] SiRNA screening of the kinome identifies ULK1 as a multidomain modulator of autophagy [J].

Chan, Edmond Y. W. ;

Kir, Serkan ;

Tooze, Sharon A. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (35) :25464-25474

[3] Isolation of the protein kinase TAO2 and identification of its mitogen-activated protein kinase/extracellular signal-regulated kinase kinase binding domain [J].

Chen, Z ;

Hutchison, M ;

Cobb, MH .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (40) :28803-28807

[4]

Choi AMK, 2013, NEW ENGL J MED, V368, P1845, DOI [10.1056/NEJMra1205406, 10.1056/NEJMc1303158]

[5] Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal [J].

Gao, Jianjiong ;

Aksoy, Buelent Arman ;

Dogrusoz, Ugur ;

Dresdner, Gideon ;

Gross, Benjamin ;

Sumer, S. Onur ;

Sun, Yichao ;

Jacobsen, Anders ;

Sinha, Rileen ;

Larsson, Erik ;

Cerami, Ethan ;

Sander, Chris ;

Schultz, Nikolaus .

SCIENCE SIGNALING, 2013, 6 (269) :pl1

[6] LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing [J].

Kabeya, Y ;

Mizushima, N ;

Uero, T ;

Yamamoto, A ;

Kirisako, T ;

Noda, T ;

Kominami, E ;

Ohsumi, Y ;

Yoshimori, T .

EMBO JOURNAL, 2000, 19 (21) :5720-5728

[7] Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance [J].

Karsli-Uzunbas, Gizem ;

Guo, Jessie Yanxiang ;

Price, Sandy ;

Teng, Xin ;

Laddha, Saurabh V. ;

Khor, Sinan ;

Kalaany, Nada Y. ;

Jacks, Tyler ;

Chan, Chang S. ;

Rabinowitz, Joshua D. ;

White, Eileen .

CANCER DISCOVERY, 2014, 4 (08) :914-927

[8] MAPKAP kinase-2 is a cell cycle checkpoint kinase that regulates the G2/M transition and S phase progression in response to UV irradiation [J].

Manke, IA ;

Nguyen, A ;

Lim, D ;

Stewart, MQ ;

Elia, AEH ;

Yaffe, MB .

MOLECULAR CELL, 2005, 17 (01) :37-48

[9] PSK, a novel STE20-like kinase derived from prostatic carcinoma that activates the c-Jun N-terminal kinase mitogen-activated protein kinase pathway and regulates actin cytoskeletal organization [J].

Moore, TM ;

Garg, R ;

Johnson, C ;

Coptcoat, MJ ;

Ridley, AJ ;

Morris, JDH .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (06) :4311-4322

[10] p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy [J].

Pankiv, Serhiy ;

Clausen, Terje Hoyvarde ;

Lamark, Trond ;

Brech, Andreas ;

Bruun, Jack-Ansgar ;

Outzen, Heidi ;

Overvatn, Aud ;

Bjorkoy, Geir ;

Johansen, Terje .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (33) :24131-24145

← 1 2 →