Rational design of 5-((1H-imidazol-1-yl)methyl)quinolin-8-ol derivatives as novel bromodomain-containing protein 4 inhibitors

Eur J Med Chem. 2019 Feb 1:163:281-294. doi: 10.1016/j.ejmech.2018.11.018.

Jing Xing ¹, Rukang Zhang ¹, Xiangrui Jiang ², Tianwen Hu ³, Xinjun Wang ⁴, Gang Qiao ⁴, Junjian Wang ⁵, Fengling Yang ⁶, Xiaomin Luo ³, Kaixian Chen ⁷, Jingshan Shen ⁸, Cheng Luo ⁹, Hualiang Jiang ¹⁰, Mingyue Zheng ¹¹

Affiliations

1 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China.
2 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
3 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
4 Suplead Co., LTD, Building D, 389 Ruoshui Road, Suzhou, 215000, China.
5 College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, 450001, China.
6 College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, 450001, China; College of Life Science and Engineering, Henan University of Urban Construction, Pingdingshan, 467036, China.
7 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 200031, China.
8 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China. Electronic address: shenjingshan@simm.ac.cn.
9 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China; CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China. Electronic address: cluo@simm.ac.cn.
10 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China; CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 200031, China.
11 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China. Electronic address: myzheng@simm.ac.cn.

PMID: 30529546 DOI: 10.1016/j.ejmech.2018.11.018

Abstract

Bromodomain-containing protein 4 (BRD4), an epigenetic reader of acetyl lysine, has emerged as a promising therapeutic target for many diseases including Cancer, inflammation and heart failure. Our previous study reported that nitroxoline, an FDA approved Antibiotic, showed potential BRD4 inhibitory activity and antiproliferation activity against leukemia cell lines. In this study, we further explored the structure-activity relationship (SAR) around nitroxoline and employed our previously developed machine learning based activity scoring function BRD4LGR for further analysis. To improve the cellular level activity, physico-chemical properties were optimized using computational approaches. Then the candidates were tested for their ADME/T profiles. Finally, based on this rational hit-to-lead optimization strategy, 3 drug-like BRD4 inhibitors were obtained, with different profiles on cell line selectivity for multiple myeloma, leukemia and triple negative breast Cancer. Further mechanism study showed these compounds could down-regulate c-Myc to inhibit Cancer cell growth. This work illustrates the application of multiple computer-aided drug design techniques in a hit-to-lead optimization scenario, and provides novel potent BRD4 inhibitors with different phenotype propensities for future Cancer treatment.

Keywords

8-OH-Quinoline; Anti-cancer activity; Bromodomain-containing protein 4; Computer-aided drug design; Early ADME/T evaluation; Rational hit-to-lead optimization.

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