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

Zhao，Lei1,2; Fan，Tingting2,3; Shi，Zhichao1,2; Ding，Chao2; Zhang，Cunlong2; Yuan，Zigao2; Sun，Qinsheng2; Tan，Chunyan2; Chu，Bizhu5; Jiang，Yuyang1,2,3,4,5

2021-03-05

10.1016/j.ejmech.2021.113173

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY   影响因子和分区

0223-5234

1768-3254

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 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 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.

Drug design EGFRT790M mutant HDAC Multitargeted compounds NSCLC

SCI

英语

其他

Shenzhen Development and Reform Committee[20151961,2019156] ; Department of Science and Technology of Guangdong Province[2017B030314083] ; Shenzhen Bay Laboratory Open Funding[SZBL2019062801009]

Pharmacology & Pharmacy

Chemistry, Medicinal

WOS:000629626600042

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER

CHEMISTRY

2-s2.0-85099610886

Scopus

1.Department of Chemistry,Tsinghua University,Beijing,100084,China
2.State Key Laboratory of Chemical Oncogenomics,Key Laboratory of Chemical Biology,Tsinghua Shenzhen International Graduate School,Tsinghua University,Shenzhen,518055,China
3.Department of Chemistry Southern University of Science and Technology,Shenzhen,518055,China
4.Department of Pharmacology and Pharmaceutical Sciences,School of Medicine,Tsinghua University,Beijing,100084,China
5.Institute of Biomedical Health Technology and Engineering,Shenzhen Bay Laboratory,Shenzhen,518132,China

Zhao，Lei,Fan，Tingting,Shi，Zhichao,et al. Design, synthesis and evaluation of novel ErbB/HDAC multitargeted inhibitors with selectivity in EGFRT790M mutant cell lines[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2021,213.

Zhao，Lei.,Fan，Tingting.,Shi，Zhichao.,Ding，Chao.,Zhang，Cunlong.,...&Jiang，Yuyang.(2021).Design, synthesis and evaluation of novel ErbB/HDAC multitargeted inhibitors with selectivity in EGFRT790M mutant cell lines.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,213.

Zhao，Lei,et al."Design, synthesis and evaluation of novel ErbB/HDAC multitargeted inhibitors with selectivity in EGFRT790M mutant cell lines".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 213(2021).