Structure-based discovery of a specific TLR1-TLR2 small molecule agonist from the ZINC drug library database

被引：22

作者：

Chen, Zhipeng ^{[1
,2
]}

Cen, Xiaohong ^{[1
,2
]}

Yang, Junjie ^{[1
,2
]}

Tang, Xiaoshan ^{[1
,2
]}

Cui, Kai ^{[3
]}

Cheng, Kui ^{[1
,2
]}

机构：

[1] Southern Med Univ, Sch Pharmaceut Sci, State Key Lab Organ Failure Res, Guangdong Prov Key Lab New Drug Screening, Guangzhou, Guangdong, Peoples R China

[2] Southern Med Univ, Sch Pharmaceut Sci, Guangzhou Key Lab Drug Res Emerging Virus Prevent, Guangzhou, Guangdong, Peoples R China

[3] Southern Med Univ, Nanfang Hosp, Dept Cardiol, Guangzhou, Guangdong, Peoples R China

来源：

CHEMICAL COMMUNICATIONS | 2018年 / 54卷 / 81期

基金：

中国国家自然科学基金;

关键词：

CELLS;

D O I：

10.1039/c8cc06618c

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

We report herein the identification of urea structure-like small molecules by structure-based virtual screening of 10.5 million compounds. Based on a variety of HEK-Blue hTLRs reporter cell assay results, we validated a TLR1/2-specific small molecule agonist, ZINC666243 (SMU127), with EC50 of 0.55 +/- 0.01 M. SMU127 stimulates NF-B activation and promotes TNF secretion in human macrophages and mononuclear cells. Moreover, the in vivo assay indicated that SMU127 could inhibit the growth of breast cancer tumors in BABL/c mice. This work has shown for the first time that a small molecule TLR1/2 agonist can inhibit breast cancer in vivo.

引用

收藏

页码：11411 / 11414

页数：4

相关论文

共 19 条

[1] Big opportunities for small molecules in immuno-oncology [J].

Adams, Jerry L. ;

Smothers, James ;

Srinivasan, Roopa ;

Hoos, Axel .

NATURE REVIEWS DRUG DISCOVERY, 2015, 14 (09) :603-622

[2] Specific activation of the TLR1-TLR2 heterodimer by small-molecule agonists [J].

Cheng, Kui ;

Gao, Meng ;

Godfroy, James I. ;

Brown, Peter N. ;

Kastelowitz, Noah ;

Yin, Hang .

SCIENCE ADVANCES, 2015, 1 (03)

[3] Discovery of Small-Molecule Inhibitors of the TLR1/TLR2 Complex [J].

Cheng, Kui ;

Wang, Xiaohui ;

Zhang, Shuting ;

Yin, Hang .

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2012, 51 (49) :12246-12249

[4] Small-Molecule Inhibitors of the TLR3/dsRNA Complex [J].

Cheng, Kui ;

Wang, Xiaohui ;

Yin, Hang .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2011, 133 (11) :3764-3767

[5] The use of a TLR2 agonist-based adjuvant for enhancing effector and memory CD8 T-cell responses [J].

Chua, Brendon Y. ;

Olson, Matthew R. ;

Bedoui, Sammy ;

Sekiya, Toshiki ;

Wong, Chinn Y. ;

Turner, Stephen J. ;

Jackson, David C. .

IMMUNOLOGY AND CELL BIOLOGY, 2014, 92 (04) :377-383

[6] Activation of MyD88-dependent TLR1/2 signaling by misfolded α-synuclein, a protein linked to neurodegenerative disorders [J].

Daniele, Stefano G. ;

Beraud, Dawn ;

Davenport, Connor ;

Cheng, Kui ;

Yin, Hang ;

Maguire-Zeiss, Kathleen A. .

SCIENCE SIGNALING, 2015, 8 (376)

[7] Anticancer TLR agonists on the ropes [J].

Guha, Malini .

NATURE REVIEWS DRUG DISCOVERY, 2012, 11 (07) :503-505

[8] Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide [J].

Jin, Mi Sun ;

Kim, Sung Eun ;

Heo, Jin Young ;

Lee, Mi Eun ;

Kim, Ho Min ;

Paik, Sang-Gi ;

Lee, Hayyoung ;

Lee, Jie-Oh .

CELL, 2007, 130 (06) :1071-1082

[9] Synergistic Anticancer Effects of Pam3CSK4 and Ara-C on B-Cell Lymphoma Cells [J].

Lee, Sae-Kyung ;

Chwee, Jyh Y. ;

Ma, Cheryl A. P. ;

Le Bert, Nina ;

Huang, Caleb W. ;

Gasser, Stephan .

CLINICAL CANCER RESEARCH, 2014, 20 (13) :3485-3495

[10] Polysaccharide Krestin Is a Novel TLR2 Agonist that Mediates Inhibition of Tumor Growth via Stimulation of CD8 T Cells and NK Cells [J].

Lu, Hailing ;

Yang, Yi ;

Gad, Ekram ;

Wenner, Cynthia A. ;

Chang, Amy ;

Larson, Emily R. ;

Dang, Yushe ;

Martzen, Mark ;

Standish, Leanna J. ;

Disis, Mary L. .

CLINICAL CANCER RESEARCH, 2011, 17 (01) :67-76