TY - JOUR
T1 - Dual nicotinamide phosphoribosyltransferase and epidermal growth factor receptor inhibitors for the treatment of cancer
AU - Zhang, Wanheng
AU - Zhang, Kuojun
AU - Yao, Yiwu
AU - Liu, Yunyao
AU - Ni, Yong
AU - Liao, Chenzhong
AU - Tu, Zhengchao
AU - Qiu, Yatao
AU - Wang, Dexiang
AU - Chen, Dong
AU - Qiang, Lei
AU - Li, Zheng
AU - Jiang, Sheng
N1 - Funding Information:
This work was supported by the National Natural Science Foundation of China ( 81773559 , 21807114 ), the Double First-Class University Project ( CPU2018GY03 ). This work was also supported by the Houston Methodist Research Institute (HMRI) and foundation (Z. L.). Dr. Dale J. Hamilton is acknowledged for manuscript review.
Publisher Copyright:
© 2020 Elsevier Masson SAS
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/2/5
Y1 - 2021/2/5
N2 - 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.
AB - 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.
KW - Antiproliferative activity
KW - Antitumor efficacy
KW - Dual inhibitor
KW - EGFR
KW - Multitarget drugs
KW - NAMPT
KW - Humans
KW - Structure-Activity Relationship
KW - Cell Survival/drug effects
KW - ErbB Receptors/antagonists & inhibitors
KW - Nicotinamide Phosphoribosyltransferase/antagonists & inhibitors
KW - Dose-Response Relationship, Drug
KW - Neoplasms, Experimental/drug therapy
KW - Female
KW - Molecular Structure
KW - Cell Proliferation/drug effects
KW - Tumor Cells, Cultured
KW - Enzyme Inhibitors/chemical synthesis
KW - Antineoplastic Agents/chemical synthesis
KW - Animals
KW - Mice, Nude
KW - Mice
KW - Mice, Inbred BALB C
KW - Molecular Docking Simulation
KW - Cytokines/antagonists & inhibitors
KW - Drug Screening Assays, Antitumor
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U2 - 10.1016/j.ejmech.2020.113022
DO - 10.1016/j.ejmech.2020.113022
M3 - Article
C2 - 33239261
AN - SCOPUS:85096557577
SN - 0223-5234
VL - 211
SP - 113022
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 113022
ER -