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Eur J Med Chem. 2017 Jul 28;135:12-23. doi: 10.1016/j.ejmech.2017.04.036. Epub 2017 Apr 14.

Design, synthesis, SAR discussion, in vitro and in vivo evaluation of novel selective EGFR modulator to inhibit L858R/T790M double mutants.

Author information

1
College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210046, PR China.
2
Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd., No. 9 Weidi Road, Nanjing 210046, PR China.
3
College of Science, Nanjing Forestry University, No. 159 Longpan Road, Nanjing 210037, PR China.
4
Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd., No. 9 Weidi Road, Nanjing 210046, PR China. Electronic address: hsh.2@163.com.
5
College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210046, PR China. Electronic address: zhyqscu@hotmail.com.

Abstract

Based upon the modeling binding mode of marketed AZD9291 with T790M, a series of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline derivatives were designed and synthesized with the purpose to overcome the drug resistance resulted from T790M/L858R double mutations. The most potent compound 8 showed excellent enzyme inhibitory activities and selectivity with sub nanomolar IC50 values for both the single L858R and double T790M/L858R mutant EGFRs, and was more than 8-fold selective for wild type EGFR. Compound 8 exhibited good microsomes stabilities and pharmacokinetic properties and lower binding affinity to hERG ion channel than AZD9291 and displayed strong antiproliferative activity against the H1975 non-small cell lung cancer (NSCLC) cells bearing T790M/L858R and in vivo anticancer efficacy in a human NSCLC (H1975) xenograft mouse model.

KEYWORDS:

5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinoline derivatives; EGFR modulator; L858R/T790M double mutants; Non-small cell lung cancer

PMID:
28426996
DOI:
10.1016/j.ejmech.2017.04.036
[Indexed for MEDLINE]

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