Discovery of novel 2,4-diarylaminopyrimidine analogues (DAAPalogues) showing potent inhibitory activities against both wild-type and mutant ALK kinases

Zilan Song, Yanhong Yang, Zhiqing Liu, Xia Peng, Junfeng Guo, Xinying Yang, Kui Wu, Jing Ai, Jian Ding, Meiyu Geng, Ao Zhang

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

We have developed a series of new 2,4-diarylaminopyrimidine analogues (DAAPalogues) bearing a flexible amino acid side chain, different from the majority of the literature reported ALK inhibitors that often possess a structurally constrained arylpiperazine fragment or its equivalents in the solvent-interaction region. Extensive structural elaboration led to compound 15 possessing IC50 values of 2.7 and 15.3 nM, respectively, in the ALK wild-type and gate-keeper mutant L1196M enzymatic assays. This compound not only showed high proliferative inhibition against ALK-addicted cells across different oncogenic forms but also effectively suppressed several ALK secondary mutant cells, including the gate-keeper L1196M and F1174L. Significant antitumor efficacy was achieved in the ALK-driven SUP-M2 xenograft model.

Original languageEnglish (US)
Pages (from-to)197-211
Number of pages15
JournalJournal of Medicinal Chemistry
Volume58
Issue number1
DOIs
StatePublished - Jan 8 2015
Externally publishedYes

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Phosphotransferases
Enzyme Assays
Heterografts
Inhibitory Concentration 50
Amino Acids

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Medicine(all)

Cite this

Discovery of novel 2,4-diarylaminopyrimidine analogues (DAAPalogues) showing potent inhibitory activities against both wild-type and mutant ALK kinases. / Song, Zilan; Yang, Yanhong; Liu, Zhiqing; Peng, Xia; Guo, Junfeng; Yang, Xinying; Wu, Kui; Ai, Jing; Ding, Jian; Geng, Meiyu; Zhang, Ao.

In: Journal of Medicinal Chemistry, Vol. 58, No. 1, 08.01.2015, p. 197-211.

Research output: Contribution to journalArticle

Song, Zilan ; Yang, Yanhong ; Liu, Zhiqing ; Peng, Xia ; Guo, Junfeng ; Yang, Xinying ; Wu, Kui ; Ai, Jing ; Ding, Jian ; Geng, Meiyu ; Zhang, Ao. / Discovery of novel 2,4-diarylaminopyrimidine analogues (DAAPalogues) showing potent inhibitory activities against both wild-type and mutant ALK kinases. In: Journal of Medicinal Chemistry. 2015 ; Vol. 58, No. 1. pp. 197-211.
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AU - Peng, Xia

AU - Guo, Junfeng

AU - Yang, Xinying

AU - Wu, Kui

AU - Ai, Jing

AU - Ding, Jian

AU - Geng, Meiyu

AU - Zhang, Ao

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