Design, synthesis and biological evaluation N2-(2-alkyoxy-6-aliphatic aminopyridin-3-yl)-2,4-diaminepyrimidine derivatives bearing acylamino or DBTD 'head' as potential ALK inhibitors

Lingyun Xing; Tongfei Jing; Junlong Zhang; Ming Guo; Xiuqi Miao; Feng Jiang; Xin Zhai

doi:10.1016/j.bioorg.2018.09.019

Design, synthesis and biological evaluation N²-(2-alkyoxy-6-aliphatic aminopyridin-3-yl)-2,4-diaminepyrimidine derivatives bearing acylamino or DBTD 'head' as potential ALK inhibitors

Bioorg Chem. 2018 Dec:81:689-699. doi: 10.1016/j.bioorg.2018.09.019. Epub 2018 Sep 12.

Authors

Lingyun Xing¹, Tongfei Jing¹, Junlong Zhang¹, Ming Guo¹, Xiuqi Miao¹, Feng Jiang¹, Xin Zhai²

Affiliations

¹ Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
² Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: [email protected].

PMID: 30268049
DOI: 10.1016/j.bioorg.2018.09.019

Abstract

Aiming to develop promising ALK inhibitors, two series of N²-(2-alkyoxy-6-aliphatic aminopyridin-3-yl)-2,4-diaminepyrimidine derivatives (22a-x and 23a-d) were designed according to scaffold hopping and bioisosterism principles. All compounds were efficiently synthesized by concise reactions and anti-proliferative activities on ALK-addicted H2228, Karpas299 cells and EGFR-expressive A549 cell were evaluated by MTT assay. Several compounds exhibited potential cytotoxic activities with IC₅₀ values below 0.10 μM. Five compounds (22g, 22h, 22l, 22s and 23a) were selected for further enzymatic determination, resulting in the discovery of 22l against ALK and ALK^L1196M with IC₅₀ values of 2.1 nM and 3.8 nM. Particularly, western blot and cell apoptosis assays identified 22l as a promising ALK inhibitor, which was capable of obviously inhibiting cellular ALK activity and inducing cell apoptosis. Eventually, molecular docking modes of 22l with ALK confirmed structural basis in accordance with the SARs analysis.

Keywords: 2,4-diarylaminopyrimidine; ALK inhibitor; DBTD; Pyridinyl group.

Publication types

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

MeSH terms

Acylation
Amination
Anaplastic Lymphoma Kinase / antagonists & inhibitors*
Anaplastic Lymphoma Kinase / metabolism
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Discovery
Humans
Molecular Docking Simulation
Neoplasms / drug therapy
Neoplasms / metabolism
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry*
Pyrimidines / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyrimidines
Anaplastic Lymphoma Kinase