Discovery of 2-aminopyridines bearing a pyridone moiety as potent ALK inhibitors to overcome the crizotinib-resistant mutants

Wenteng Chen; Xiao Guo; Can Zhang; Di Ke; Guolin Zhang; Yongping Yu

doi:10.1016/j.ejmech.2019.111734

Discovery of 2-aminopyridines bearing a pyridone moiety as potent ALK inhibitors to overcome the crizotinib-resistant mutants

Eur J Med Chem. 2019 Dec 1:183:111734. doi: 10.1016/j.ejmech.2019.111734. Epub 2019 Sep 24.

Authors

Wenteng Chen¹, Xiao Guo¹, Can Zhang¹, Di Ke¹, Guolin Zhang², Yongping Yu³

Affiliations

¹ Zhejiang Province Key Laboratory of Anti-Cancer Research, College of Pharmaceutical Sciences, Zhejiang University, 310058, China.
² Zhejiang Province Key Laboratory of Anti-Cancer Research, College of Pharmaceutical Sciences, Zhejiang University, 310058, China. Electronic address: guolinzhang@zju.edu.cn.
³ Zhejiang Province Key Laboratory of Anti-Cancer Research, College of Pharmaceutical Sciences, Zhejiang University, 310058, China. Electronic address: yyu@zju.edu.cn.

PMID: 31569004
DOI: 10.1016/j.ejmech.2019.111734

Abstract

Despite the initial benefit demonstrated in clinical setting with ALK inhibitors, the challenging resistant mutants (F1174L, L1196M and G1202R) invariably developed. In this work, a series of 2-aminopyridine derivatives were designed and synthesized by C-5 position incorporation of a 2-pyridone moiety and bioisosteric replacement of the C-3 position linkers. Optimization of the 2-aminopyridine derivatives led to the identification of hit 18d displaying a significant growth inhibition against a variety of ALK-addicted cancer cells. Especially in the case of ALK-positive Karpas-299 cell, 18d exhibited excellent anti-proliferative potency with an IC₅₀ value of about 40 nM. Moreover, 18d demonstrated encouraging activities against wild-type ALK (19 nM), ROS1 (2.3 nM) as well as challenging crizotinib-resistant ALK^L1196M and ALK^G1202R mutants with IC₅₀ values of 45 nM and 22 nM, respectively. Additionally flow cytometric analysis indicates that 18d inhibited Karpas-299 cell viability via G1 phase arrest. Taken together, this work provided a promising ALK inhibitor to circumvent the clinical crizotinib-resistant mutants.

Keywords: ALK inhibitors; Crizotinib-resistance; Linker; Pyridone; Solvent-front mutation.

MeSH terms

Aminopyridines* / chemical synthesis
Aminopyridines* / chemistry
Aminopyridines* / pharmacology
Anaplastic Lymphoma Kinase / antagonists & inhibitors*
Cell Line, Tumor
Cell Survival / drug effects
Crizotinib / pharmacology*
Drug Resistance, Neoplasm / drug effects*
Drug Resistance, Neoplasm / genetics
Humans
Mutation
Protein Kinase Inhibitors* / chemical synthesis
Protein Kinase Inhibitors* / chemistry
Protein Kinase Inhibitors* / pharmacology
Pyridones / chemistry*

Substances

Aminopyridines
Protein Kinase Inhibitors
Pyridones
Crizotinib
Anaplastic Lymphoma Kinase
alpha-aminopyridine