Dual nicotinamide phosphoribosyltransferase and epidermal growth factor receptor inhibitors for the treatment of cancer

Wanheng Zhang, Kuojun Zhang, Yiwu Yao, Yunyao Liu, Yong Ni, Chenzhong Liao, Zhengchao Tu, Yatao Qiu, Dexiang Wang, Dong Chen, Lei Qiang, Zheng Li, Sheng Jiang

Research output: Contribution to journalArticle

Abstract

Multitarget drugs have emerged as a promising treatment modality in modern anticancer therapy. Taking advantage of the synergy of NAMPT and EGFR inhibition, we have developed the first compounds that serve as dual inhibitors of NAMPT and EGFR. On the basis of CHS828 and erlotinib, a series of hybrid molecules were successfully designed and synthesized by merging of the pharmacophores. Among the compounds that were synthesized, compound 28 showed good NAMPT and EGFR inhibition, and excellent in vitro anti-proliferative activity. Compound 28, which is a new chemotype devoid of a Michael receptor, strongly inhibited the proliferation of several cancer cell lines, including H1975 non-small cell lung cancer cells harboring the EGFRL858R/T790M mutation. More importantly, it imparted significant in vivo antitumor efficacy in a human NSCLC (H1975) xenograft nude mouse model. This study provides promising leads for the development of novel antitumor agents and valuable pharmacological probes for the assessment of dual inhibition in NAMPT and EGFR pathway with a single inhibitor.

Original languageEnglish (US)
Article number113022
JournalEuropean Journal of Medicinal Chemistry
Volume211
DOIs
StatePublished - Feb 5 2021

Keywords

  • Antiproliferative activity
  • Antitumor efficacy
  • Dual inhibitor
  • EGFR
  • Multitarget drugs
  • NAMPT

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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