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

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.
Wenteng Chen 1,  Xiao Guo 1,  Can Zhang 1,  Di Ke 1,  Guolin Zhang 2,  Yongping Yu 3
Affiliations

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 ALKL1196M and ALKG1202R 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.

Figures