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

doi:10.1016/j.ejmech.2020.113022

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 journal › Article › peer-review

20 Scopus citations

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 EGFR^L858R/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 language	English (US)
Article number	113022
Pages (from-to)	113022
Journal	European Journal of Medicinal Chemistry
Volume	211
DOIs	https://doi.org/10.1016/j.ejmech.2020.113022
State	Published - Feb 5 2021

Keywords

Antiproliferative activity
Antitumor efficacy
Dual inhibitor
EGFR
Multitarget drugs
NAMPT
Humans
Structure-Activity Relationship
Cell Survival/drug effects
ErbB Receptors/antagonists & inhibitors
Nicotinamide Phosphoribosyltransferase/antagonists & inhibitors
Dose-Response Relationship, Drug
Neoplasms, Experimental/drug therapy
Female
Molecular Structure
Cell Proliferation/drug effects
Tumor Cells, Cultured
Enzyme Inhibitors/chemical synthesis
Antineoplastic Agents/chemical synthesis
Animals
Mice, Nude
Mice
Mice, Inbred BALB C
Molecular Docking Simulation
Cytokines/antagonists & inhibitors
Drug Screening Assays, Antitumor

ASJC Scopus subject areas

Drug Discovery
Pharmacology
Organic Chemistry

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10.1016/j.ejmech.2020.113022

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title = "Dual nicotinamide phosphoribosyltransferase and epidermal growth factor receptor inhibitors for the treatment of cancer",

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, Humans, Structure-Activity Relationship, Cell Survival/drug effects, ErbB Receptors/antagonists \& inhibitors, Nicotinamide Phosphoribosyltransferase/antagonists \& inhibitors, Dose-Response Relationship, Drug, Neoplasms, Experimental/drug therapy, Female, Molecular Structure, Cell Proliferation/drug effects, Tumor Cells, Cultured, Enzyme Inhibitors/chemical synthesis, Antineoplastic Agents/chemical synthesis, Animals, Mice, Nude, Mice, Mice, Inbred BALB C, Molecular Docking Simulation, Cytokines/antagonists \& inhibitors, Drug Screening Assays, Antitumor",

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

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Masson SAS",

year = "2021",

month = feb,

day = "5",

doi = "10.1016/j.ejmech.2020.113022",

language = "English (US)",

volume = "211",

pages = "113022",

journal = "European Journal of Medicinal Chemistry",

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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

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

UR - https://www.scopus.com/pages/publications/85096557577

UR - https://www.scopus.com/inward/citedby.url?scp=85096557577&partnerID=8YFLogxK

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 -

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

Abstract

Keywords

ASJC Scopus subject areas

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