Structure-based drug optimization and biological evaluation of tetrahydroquinolin derivatives as selective and potent CBP bromodomain inhibitors

Xiaoyang Bi; Yu Chen; Zhongya Sun; Wenchao Lu; Pan Xu; Tian Lu; Hong Ding; Naixia Zhang; Hualiang Jiang; Kaixian Chen; Bing Zhou; Cheng Luo

doi:10.1016/j.bmcl.2020.127480

Structure-based drug optimization and biological evaluation of tetrahydroquinolin derivatives as selective and potent CBP bromodomain inhibitors

Bioorg Med Chem Lett. 2020 Nov 15;30(22):127480. doi: 10.1016/j.bmcl.2020.127480. Epub 2020 Aug 31.

Authors

Xiaoyang Bi¹, Yu Chen², Zhongya Sun³, Wenchao Lu⁴, Pan Xu², Tian Lu⁵, Hong Ding⁶, Naixia Zhang⁷, Hualiang Jiang², Kaixian Chen⁸, Bing Zhou⁹, Cheng Luo¹⁰

Affiliations

¹ Department of Medicinal Chemistry, 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 University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China; 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.
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; School of Life and Technology, Harbin Institute of Technology, Harbin 150001, China.
⁴ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁵ 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; Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, China.
⁶ University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China; 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: hding@simm.ac.cn.
⁷ Department of Analytical Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
⁸ University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China; 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; Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), 1 Wenhai Road, Aoshanwei, Jimo, Qingdao 266237, China.
⁹ Department of Medicinal Chemistry, 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. Electronic address: zhoubing@simm.ac.cn.
¹⁰ University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China; 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; Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), 1 Wenhai Road, Aoshanwei, Jimo, Qingdao 266237, China. Electronic address: cluo@simm.ac.cn.

PMID: 32882416
DOI: 10.1016/j.bmcl.2020.127480

Abstract

CBP bromodomain could recognize acetylated lysine and function as transcription coactivator to regulate transcription and downstream gene expression. Furthermore, CBP has been shown to be related to many human malignancies including acute myeloid leukemia. Herein, we identified DC-CPin734 as a potent CBP bromodomain inhibitor with a TR-FRET IC₅₀ value of 19.5 ± 1.1 nM and over 400-fold of selectivity against BRD4 bromodomains through structure based rational drug design guided iterative chemical modification endeavoring to discover optimal tail-substituted tetrahydroquinolin derivatives. Moreover, DC-CPin734 showed potent inhibitory activity to AML cell line MV4-11 with an IC₅₀ value of 0.55 ± 0.04 μM, and its cellular on-target effects were further evidenced by c-Myc downregulation results. In summary, DC-CPin734 showing good potency, selectivity and anti AML activity could serve as a potent and selective in vitro and in vivo probe of CBP bromodomain and a promising lead compound for future drug development.

Keywords: Acute myeloid leukemia; Bromodomain; CBP; Drug design; Inhibitor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
CREB-Binding Protein / antagonists & inhibitors*
CREB-Binding Protein / genetics
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation
Molecular Structure
Quinolines / chemical synthesis
Quinolines / chemistry
Quinolines / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Quinolines
1,2,3,4-tetrahydroquinoline
CREB-Binding Protein