Design, synthesis and biological evaluation of novel 4-arylaminopyrimidine derivatives possessing a hydrazone moiety as dual inhibitors of L1196M ALK and ROS1

Yu Wang; Guogang Zhang; Gang Hu; Yanxin Bu; Hongrui Lei; Daiying Zuo; Mengting Han; Xin Zhai; Ping Gong

doi:10.1016/j.ejmech.2016.06.056

Design, synthesis and biological evaluation of novel 4-arylaminopyrimidine derivatives possessing a hydrazone moiety as dual inhibitors of L1196M ALK and ROS1

Eur J Med Chem. 2016 Nov 10:123:80-89. doi: 10.1016/j.ejmech.2016.06.056. Epub 2016 Jul 12.

Authors

Yu Wang¹, Guogang Zhang², Gang Hu¹, Yanxin Bu¹, Hongrui Lei¹, Daiying Zuo³, Mengting Han³, Xin Zhai⁴, Ping Gong⁵

Affiliations

¹ Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
² State Key Laboratory Breeding Base-Hebei Province Key Laboratory of Molecular Chemistry for Drug, College of Chemical & Pharmaceutical Engineering, Hebei University of Science & Technology, Shijiazhuang 050018, PR China.
³ Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
⁴ Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China. Electronic address: leixinjia@126.com.
⁵ Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China. Electronic address: gongpinggp@126.com.

PMID: 27474925
DOI: 10.1016/j.ejmech.2016.06.056

Abstract

A series of 4-arylaminopyrimidine derivatives possessing a hydrazone moiety were designed, synthesized and evaluated for their biological activity. Most compounds exhibited moderate to excellent cytotoxic activity against ALK-addicted KARPAS299 and ROS1-addicted HCC78, while also showing much less potent activity against A549, H460 and HT-29, whose growth were not dependent on ALK and/or ROS1, as compared with crizotinib and ceritinib. The most promising compound, 7b, showed high antiproliferative effects on ALK-addicted KARPAS299 and ROS1-addicted HCC78 cell lines with IC50 of 20 nM and 28 nM, respectively, but showed no inhibitory activity against A549, H460 and HT-29. The enzymatic assay identified 7b as a potent and selective ALK and ROS1 dual inhibitor with IC50 of 2.5 nM and 2.7 nM, respectively. It also exhibited good inhibitory activity against the L1196M ALK with an IC50 value of 67 nM.

Keywords: 4-Arylaminopyrimidine derivatives; Dual inhibitor; Hydrazone moiety; L1196M ALK; ROS1.

MeSH terms

Anaplastic Lymphoma Kinase
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Design
Humans
Hydrazones / chemistry
Inhibitory Concentration 50
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology
Protein-Tyrosine Kinases / antagonists & inhibitors*
Proto-Oncogene Proteins / antagonists & inhibitors*
Pyrimidines / chemistry*
Pyrimidines / pharmacology
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Hydrazones
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Pyrimidines
2-aminopyrimidine
ALK protein, human
Anaplastic Lymphoma Kinase
Protein-Tyrosine Kinases
ROS1 protein, human
Receptor Protein-Tyrosine Kinases