Design, synthesis and evaluation of novel ErbB/HDAC multitargeted inhibitors with selectivity in EGFRT790M mutant cell lines

Lei Zhao; Tingting Fan; Zhichao Shi; Chao Ding; Cunlong Zhang; Zigao Yuan; Qinsheng Sun; Chunyan Tan; Bizhu Chu; Yuyang Jiang

doi:10.1016/j.ejmech.2021.113173

Design, synthesis and evaluation of novel ErbB/HDAC multitargeted inhibitors with selectivity in EGFR^T790M mutant cell lines

Eur J Med Chem. 2021 Mar 5:213:113173. doi: 10.1016/j.ejmech.2021.113173. Epub 2021 Jan 18.

Authors

Lei Zhao¹, Tingting Fan², Zhichao Shi¹, Chao Ding³, Cunlong Zhang³, Zigao Yuan³, Qinsheng Sun³, Chunyan Tan³, Bizhu Chu⁴, Yuyang Jiang⁵

Affiliations

¹ Department of Chemistry, Tsinghua University, Beijing, 100084, PR China; State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, PR China.
² State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, PR China; Department of Chemistry Southern University of Science and Technology, Shenzhen, 518055, PR China.
³ State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, PR China.
⁴ Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, PR China. Electronic address: chubz@szbl.ac.cn.
⁵ Department of Chemistry, Tsinghua University, Beijing, 100084, PR China; State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, PR China; Department of Chemistry Southern University of Science and Technology, Shenzhen, 518055, PR China; Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, 100084, PR China; Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, PR China. Electronic address: jiangyy@sz.tsinghua.edu.cn.

PMID: 33493830
DOI: 10.1016/j.ejmech.2021.113173

Abstract

Acquired resistance leads to the failure of EGFR TKIs in NSCLC treatment. A novel series of hydroxamic acid-containing 4-aminoquinazoline derivatives as irreversible ErbB/HDAC multitargeted inhibitors for NSCLC therapy had been designed and synthesized, which displayed weak anti-proliferative activity in several EGFR wild-type cancer cell lines (NCI-H838, SK-BR-3, A549, A431) yet retained moderate activity to EGFR^T790M resistance mutation harboring NCI-H1975 cells. The mechanistic studies revealed that the representative compound 11e was able to inhibit the phosphorylation of EGFR, up-regulate hyperacetylation of histone H3 and even reduce the expression of EGFR and Akt in NCI-H1975 cells. In further assays, compound 11e also showed moderate anti-proliferative activity in other EGFR^T790M harboring tumor cell lines (NCI-H820, Ba/F3_EGFR_Del19-T790M-C797S) and low toxicities in normal cell lines (HL-7702, FHC). This selectivity of designed multitargeted compounds could serve as a potential strategy to circumvent multiple mechanisms of acquired resistance to EGFR-targeted therapy without severe toxicities and side effects resulting from broad inhibition.

Keywords: Drug design; EGFR(T790M) mutant; HDAC; Multitargeted compounds; NSCLC.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design
Drug Screening Assays, Antitumor
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / genetics
ErbB Receptors / metabolism
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / chemistry
Histone Deacetylase Inhibitors / pharmacology*
Humans
Hydroxamic Acids / chemical synthesis
Hydroxamic Acids / chemistry
Hydroxamic Acids / pharmacology*
Molecular Docking Simulation
Molecular Structure
Mutation
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Quinazolines / chemical synthesis
Quinazolines / chemistry
Quinazolines / pharmacology*
Structure-Activity Relationship

Substances

4-aminoquinazoline
Antineoplastic Agents
Histone Deacetylase Inhibitors
Hydroxamic Acids
Protein Kinase Inhibitors
Quinazolines
EGFR protein, human
ErbB Receptors