Fragment-based modification of 2,4-diarylaminopyrimidine derivatives as ALK and ROS1 dual inhibitors to overcome secondary mutants

Minglin Zhu; Wei Li; Tianming Zhao; Yuxiang Chen; Tong Li; Shangfei Wei; Ming Guo; Xin Zhai

doi:10.1016/j.bmc.2020.115719

Fragment-based modification of 2,4-diarylaminopyrimidine derivatives as ALK and ROS1 dual inhibitors to overcome secondary mutants

Bioorg Med Chem. 2020 Oct 15;28(20):115719. doi: 10.1016/j.bmc.2020.115719. Epub 2020 Aug 25.

Authors

Minglin Zhu¹, Wei Li², Tianming Zhao¹, Yuxiang Chen¹, Tong Li¹, Shangfei Wei¹, Ming Guo¹, Xin Zhai³

Affiliations

¹ Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
² Drug Research and Development Center, Shandong Drug and Food Vocational College, Weihai 264200, PR China.
³ Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: zhaixin_syphu@126.com.

PMID: 33069075
DOI: 10.1016/j.bmc.2020.115719

Abstract

In order to explore novel ALK and ROS1 dual inhibitors capable of overcoming crizotinib-resistant mutants, two series of 2,4-diarylaminopyrimidine derivatives were designed, synthesized and evaluated for their in vitro cytotoxic activity. In this work, we retained the 2,4-diarylaminopyrimidine scaffold and derivatize the DAAP scaffold with sulfonyl and acrylamide moieties to extend the structure-activity relationship (SAR) study. To our delight, some compounds exhibited excellent inhibitory activity with a double-digit nanomolar level in MTT assay. Four compounds were selected for enzymic assays further, the results led to the identification of a potent ALK and ROS1 dual inhibitor X-17, with IC₅₀ values of 3.7 nM, 2.3 nM, 8.9 nM and 1.9 nM against ALK, ALK^L1196M, ALK^G1202R and ROS1, respectively. Ultimately, the molecular docking studies on X-17 clearly disclosed reasonable and optimal binding interactions with ALK.

Keywords: 2,4-Diarylaminopyrimidine; ALK; Crizotinib-resistant; Dual inhibitor; ROS1.

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 / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation
Molecular Structure
Mutation
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / genetics
Protein-Tyrosine Kinases / metabolism
Proto-Oncogene Proteins / antagonists & inhibitors*
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship

Substances

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