Discovery and antitumor activity of Benzo[d]imidazol-containing 2,4-diarylaminopyrimidine analogues as ALK inhibitors with mutation-combating effects

Zheng Li; Ming Guo; Meng Cao; Tianming Zhao; Mingzhu Li; Xin Zhai

doi:10.1016/j.bmc.2021.116108

Discovery and antitumor activity of Benzo[d]imidazol-containing 2,4-diarylaminopyrimidine analogues as ALK inhibitors with mutation-combating effects

Bioorg Med Chem. 2021 May 1:37:116108. doi: 10.1016/j.bmc.2021.116108. Epub 2021 Mar 14.

Authors

Zheng Li¹, Ming Guo², Meng Cao², Tianming Zhao², Mingzhu Li³, Xin Zhai⁴

Affiliations

¹ Department of Integrated Traditional Chinese and Western Medicine Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang 110042, China.
² Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
³ Department of Integrated Traditional Chinese and Western Medicine Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang 110042, China. Electronic address: limingzhu198600@126.com.
⁴ Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: zhaixin_syphu@126.com.

PMID: 33756437
DOI: 10.1016/j.bmc.2021.116108

Abstract

To address drug resistance caused by ALK kinase mutations, a series of novel 2,4-diarylaminopyrimidine (DAAP) analogues were designed by incorporating 1H-benzo[d]imidazol motif onto the maternal framework. All compounds were efficiently synthesized and antiproliferative activities against Karpas299, H2228 and A549 cell lines were evaluated by MTT assay. Delightly, the most promising derivative H-11 was detected with IC₅₀ values of 0.016 μM and 0.099 μM against ALK- positive Karpas299 and H2228 cells. Meanwhile, H-11 displayed encouraging enzymatic inhibitory potency with IC₅₀ values of 2.7 nM, 3.8 nM and 5.7 nM toward ALK^WT, ALK^L1196M and ALK^G1202R, respectively. Ultimately, the binding modes of optimal H-11 with ALK wild-type and mutants were ideally established which further confirmed the structural basis in accordance with the SARs analysis.

Keywords: 2,4-Diarylaminopyrimidine; ALK; Antitumor evaluations; G1202R mutant; Synthesis.

Publication types

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

MeSH terms

Anaplastic Lymphoma Kinase / antagonists & inhibitors*
Anaplastic Lymphoma Kinase / genetics
Anaplastic Lymphoma Kinase / metabolism
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology*
Benzimidazoles / chemical synthesis
Benzimidazoles / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Screening Assays, Antitumor
Enzyme Assays
Humans
Molecular Docking Simulation
Molecular Structure
Mutation
Protein Binding
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Benzimidazoles
Protein Kinase Inhibitors
Pyrimidines
ALK protein, human
Anaplastic Lymphoma Kinase