Discovery of novel 2,4-diarylaminopyrimidine analogues (DAAPalogues) showing potent inhibitory activities against both wild-type and mutant ALK kinases

Zilan Song; Yanhong Yang; Zhiqing Liu; Xia Peng; Junfeng Guo; Xinying Yang; Kui Wu; Jing Ai; Jian Ding; Meiyu Geng; Ao Zhang

doi:10.1021/jm5005144

Discovery of novel 2,4-diarylaminopyrimidine analogues (DAAPalogues) showing potent inhibitory activities against both wild-type and mutant ALK kinases

J Med Chem. 2015 Jan 8;58(1):197-211. doi: 10.1021/jm5005144. Epub 2014 May 8.

Authors

Zilan Song¹, Yanhong Yang, Zhiqing Liu, Xia Peng, Junfeng Guo, Xinying Yang, Kui Wu, Jing Ai, Jian Ding, Meiyu Geng, Ao Zhang

Affiliation

¹ CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences , Shanghai 201203, China.

PMID: 24785465
DOI: 10.1021/jm5005144

Abstract

We have developed a series of new 2,4-diarylaminopyrimidine analogues (DAAPalogues) bearing a flexible amino acid side chain, different from the majority of the literature reported ALK inhibitors that often possess a structurally constrained arylpiperazine fragment or its equivalents in the solvent-interaction region. Extensive structural elaboration led to compound 15 possessing IC50 values of 2.7 and 15.3 nM, respectively, in the ALK wild-type and gate-keeper mutant L1196M enzymatic assays. This compound not only showed high proliferative inhibition against ALK-addicted cells across different oncogenic forms but also effectively suppressed several ALK secondary mutant cells, including the gate-keeper L1196M and F1174L. Significant antitumor efficacy was achieved in the ALK-driven SUP-M2 xenograft model.

Publication types

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

MeSH terms

Acetanilides / chemistry*
Acetanilides / pharmacology*
Anaplastic Lymphoma Kinase
Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology
Area Under Curve
Cell Line
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery
Female
Humans
Mice
Mice, Nude
Models, Chemical
Molecular Structure
Mutant Proteins / antagonists & inhibitors*
Mutant Proteins / metabolism
Mutation
NIH 3T3 Cells
Neoplasms / drug therapy
Neoplasms / pathology
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology*
Rats
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Receptor Protein-Tyrosine Kinases / genetics
Receptor Protein-Tyrosine Kinases / metabolism
Sulfones / chemistry*
Sulfones / pharmacology*
Tumor Burden / drug effects
Xenograft Model Antitumor Assays

Substances

2-amino-N-(3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)acetamide
Acetanilides
Antineoplastic Agents
Mutant Proteins
Protein Kinase Inhibitors
Sulfones
ALK protein, human
Alk protein, mouse
Alk protein, rat
Anaplastic Lymphoma Kinase
Receptor Protein-Tyrosine Kinases