1. Academic Validation
  2. Discovery of novel 2,4-diarylaminopyrimidine analogues as ALK and ROS1 dual inhibitors to overcome crizotinib-resistant mutants including G1202R

Discovery of novel 2,4-diarylaminopyrimidine analogues as ALK and ROS1 dual inhibitors to overcome crizotinib-resistant mutants including G1202R

  • Eur J Med Chem. 2018 Jan 1;143:123-136. doi: 10.1016/j.ejmech.2017.11.008.
Yu Wang 1 Shaowei Chen 1 Gang Hu 1 Jiao Wang 1 Wenfeng Gou 2 Daiying Zuo 2 Yucheng Gu 3 Ping Gong 4 Xin Zhai 5
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
  • 2 Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
  • 3 Syngenta, Jealott's Hill International Research Centre, Bracknell, Berkshire RG42 6EY, UK.
  • 4 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China. Electronic address: gongpinggp@126.com.
  • 5 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China. Electronic address: zhaixin_syphu@126.com.
Abstract

Aiming to explore novel anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine-protein kinase ROS (ROS1) dual inhibitors to overcome crizotinib-resistant mutants, two series of 2,4-diarylaminopyrimidine (DAAP) analogues bearing thiazole or 1,2,3-triazole moieties were designed and synthesized based upon the cocrystal structure of ceritinib with ALKWT (PDB 4MKC) as well as the binding model of ceritinib with ALKG1202R. The cellular and enzymatic assays validated 34c (WY-135) as a promising ALK (IC50 = 1.4 nM) and ROS1 (IC50 = 1.1 nM) dual inhibitor superior to crizotinib and ceritinib. 34c showed significantly inhibitory activities on ALK-dependent cell lines KARPAS299 (IC50 = 21 nM) and H2228 (IC50 = 95 nM) as well as ROS1-positive cell line HCC78 (IC50 = 40 nM). In particular, 34c was potent against a variety of frequently observed crizotinib-resistant mutants, particularly the L1196M mutant (IC50 = 3.1 nM) identified as the "gatekeeper" mutation and the G1202R mutant (IC50 = 8.7 nM) which conferred resistance to all clinical stage ALK inhibitors. Furthermore, 34c was capable of inducing cell Apoptosis and strongly inhibiting cellular ALK and ROS1 activity. In addition, the binding models of 34c with ALKWT, ALKL1196M and ALKG1202R provided structural bases for SARs observations.

Keywords

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

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