Structure-based optimization identified novel furyl-containing 2,4-diarylaminopyrimidine analogues as ALK/ROS1 dual inhibitors with anti-mutation effects

Ming Guo; Daiying Zuo; Tianming Zhao; Xiangyu Li; Jianshuang Cao; Yuxuan Qiu; Shangfei Wei; Xin Zhai

doi:10.1016/j.ejmech.2021.113259

Structure-based optimization identified novel furyl-containing 2,4-diarylaminopyrimidine analogues as ALK/ROS1 dual inhibitors with anti-mutation effects

Eur J Med Chem. 2021 Mar 15:214:113259. doi: 10.1016/j.ejmech.2021.113259. Epub 2021 Feb 3.

Authors

Ming Guo¹, Daiying Zuo², Tianming Zhao¹, Xiangyu Li¹, Jianshuang Cao¹, Yuxuan Qiu¹, Shangfei Wei¹, Xin Zhai³

Affiliations

¹ Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
² Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016, China.
³ Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: zhaixin_syphu@126.com.

PMID: 33581554
DOI: 10.1016/j.ejmech.2021.113259

Abstract

Aiming to develop ALK/ROS1 dual inhibitors overcoming ceritinib-resistant G1202R mutant, a dedicated structure-guided modification campaign was conducted based on ALK co-crystal structures. Twenty eight diarylaminopyrimidine (DAAP) analogues possessing furan or tetrahydrofuran group were designed and synthesized, among which compound 16 bearing (dimethylamino)methyl)furan-2-yl)methyl)thio fragment was identified. Compound 16 exhibited significant cytotoxicity on ALK-positive Karpas299 and H2228 cells with IC₅₀ values of 20 nM and 110 nM. Meanwhile, compound 16 turned out as the most potent entity superior to ceritinib with IC₅₀ values of 2.8, 2.6, 3.8 and 2.3 nM against ALK^WT, ALK^L1196M, ALK^G1202R and ROS1^WT, respectively. Subsequently, western blot assay showed that compound 16 significantly suppressed ALK and its downstream protein expression in a dose-dependent manner. Alternatively, the Hoechst 33258 and AO/EB staining assays illustrated that compound 16 could induce H2228 cell apoptosis. Ultimately, the binding models of compound 16 with ALK^WT, ALK^G1202R as well as ROS1 clearly presented the essential interactions within the active site. Together, compound 16 was validated as a promising ALK/ROS1 dual inhibitor for ALK^G1202R mutation correlated tumors.

Keywords: 2,4-Diarylaminopyrimidines; ALK/ROS1; Biological evaluations; Dual inhibitors; G1202R mutant; Synthesis.

MeSH terms

Anaplastic Lymphoma Kinase / antagonists & inhibitors*
Anaplastic Lymphoma Kinase / genetics
Anaplastic Lymphoma Kinase / metabolism
Cell Line, Tumor
Dose-Response Relationship, Drug
Humans
Models, Molecular
Molecular Structure
Mutation / drug effects
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

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