Discovery of pyrido[3,4-b]indol-1-one derivatives as novel non-covalent Bruton's tyrosine kinase (BTK) inhibitors

Dou Dou; Wenjie Sha; Yanyan Diao; Rongrong Su; Yunjin Qiao; Zhixiao Yu; Zhenjiang Zhao; Honglin Li; Zhuo Chen; Yufang Xu

doi:10.1016/j.bioorg.2021.105541

Discovery of pyrido[3,4-b]indol-1-one derivatives as novel non-covalent Bruton's tyrosine kinase (BTK) inhibitors

Bioorg Chem. 2022 Feb:119:105541. doi: 10.1016/j.bioorg.2021.105541. Epub 2021 Dec 7.

Authors

Dou Dou¹, Wenjie Sha¹, Yanyan Diao¹, Rongrong Su¹, Yunjin Qiao¹, Zhixiao Yu¹, Zhenjiang Zhao¹, Honglin Li², Zhuo Chen³, Yufang Xu⁴

Affiliations

¹ Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China.
² Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China. Electronic address: hlli@ecust.edu.cn.
³ Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China. Electronic address: chenzhuo@ecust.edu.cn.
⁴ Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China. Electronic address: yfxu@ecust.edu.cn.

PMID: 34910982
DOI: 10.1016/j.bioorg.2021.105541

Abstract

Bruton's tyrosine kinase (BTK) is an attractive target for the treatment of malignancy and inflammatory/autoimmune diseases. Most of the covalent BTK inhibitors would induce off-target side effects and drug resistance. To improve the drug safety of BTK inhibitors, non-covalent inhibitors have attracted more and more attention. We designed a series of novel pyrido[3,4-b]indol-1-one derivatives (N-A and N-B) via scaffold hopping from CGI-1746. The structure-activity relationship (SAR) of the newly-synthesized compounds was explored. The results showed that compounds 12 and 18 exhibited potent enzymatic potency against BTK with IC₅₀ values of 0.22 μM and 0.19 μM, respectively. In lymphoma cell lines U-937 cells and Ramos cells, compounds 12 and 18 displayed comparative antiproliferative activity with Ibrutinib. Moreover, compound 12 induced G1-phase cell cycle arrest and apoptosis in U-937 cells. And it could effectively inhibit tumor growth in U-937 xenograft mouse model (TGI = 41.90% at 50 mg/kg). In all, the new pyrido[3,4-b]indol-1-one derivatives have the antitumor potency by BTK inhibition and were worthy of further exploration.

Keywords: BTK; Inhibitors; Non-covalent inhibitors; Scaffold hopping; Structure-activity relationship.

Publication types

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

MeSH terms

Agammaglobulinaemia Tyrosine Kinase / antagonists & inhibitors*
Agammaglobulinaemia Tyrosine Kinase / metabolism
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Cycle Checkpoints / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Humans
Indoles / chemical synthesis
Indoles / chemistry
Indoles / pharmacology*
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Indoles
Protein Kinase Inhibitors
Agammaglobulinaemia Tyrosine Kinase