2. Academic Validation
  3. Dual nicotinamide phosphoribosyltransferase and epidermal growth factor receptor inhibitors for the treatment of cancer

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

  • Eur J Med Chem. 2021 Feb 5:211:113022. doi: 10.1016/j.ejmech.2020.113022.
Wanheng Zhang 1,  Kuojun Zhang 1,  Yiwu Yao 1,  Yunyao Liu 1,  Yong Ni 1,  Chenzhong Liao 2,  Zhengchao Tu 3,  Yatao Qiu 1,  Dexiang Wang 1,  Dong Chen 1,  Lei Qiang 1,  Zheng Li 4,  Sheng Jiang 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China.
  • 2 School of Biological and Medical Engineering, Hefei University of Technology, Hefei, 230009, China.
  • 3 Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 10530, China.
  • 4 Center for Bioenergetics, Houston Methodist Research Institute, 6670 Bertner, Houston, TX, 77030, United States. Electronic address: zli@houstonmethodist.org.
  • 5 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: jiangsh9@gmail.com.
PMID: 33239261 DOI: 10.1016/j.ejmech.2020.113022
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.

Keywords

Antiproliferative activity; Antitumor efficacy; Dual inhibitor; EGFR; Multitarget drugs; NAMPT.

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