摘要

Novel dual inhibitors of histone deacetylase (HDAC) and heat-shock protein 90 (HSP90) are synthesized and evaluated. These compounds are endowed with potent HDAC and HSP90 inhibitory activities with IC50 values in nanomolar range with Compound 20 (HDAC IC50 = 194 nM; HSP90α IC50 = 153 nM) and compound 26 (HDAC IC50 = 360 nM; HSP90α IC50 = 77 nM) displaying most potent HDAC and HSP90α inhibitory activities. Both of these compounds induce HSP70 expression and down regulate HSP90 client proteins which play important roles in the regulation of survival and invasiveness in cancer cells. In addition, compounds 20 and 26 induce acetylation of α-tubulin and histone H3. Significantly, compounds 20 and 26 could effectively reduce programmed death-ligand 1 (PD-L1) expression in IFN-γ treated lung H1975 cells in a dose dependent manner. These findings suggest that dual inhibition of HDAC and HSP90 that can modulate immunosuppressive ability of tumor area may provide a better therapeutic strategy for cancer treatment in the future.
原文英語
文章編號111725
頁(從 - 到)111725
期刊European Journal of Medicinal Chemistry
185
DOIs
出版狀態已發佈 - 一月 1 2020

指紋

Anilides
HSP90 Heat-Shock Proteins
Histone Deacetylase Inhibitors
Histone Deacetylases
Down-Regulation
Ligands
Inhibitory Concentration 50
Acetylation
Neoplasms
Oncology
Tubulin
Immunosuppressive Agents
Histones
Tumors
Cells
Lung

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

引用此文

@article{1a96f796b62e44f387b514e233126ee5,
title = "N-alkyl-hydroxybenzoyl anilide hydroxamates as dual inhibitors of HDAC and HSP90, downregulating IFN-γ induced PD-L1 expression",
abstract = "Novel dual inhibitors of histone deacetylase (HDAC) and heat-shock protein 90 (HSP90) are synthesized and evaluated. These compounds are endowed with potent HDAC and HSP90 inhibitory activities with IC50 values in nanomolar range with Compound 20 (HDAC IC50 = 194 nM; HSP90α IC50 = 153 nM) and compound 26 (HDAC IC50 = 360 nM; HSP90α IC50 = 77 nM) displaying most potent HDAC and HSP90α inhibitory activities. Both of these compounds induce HSP70 expression and down regulate HSP90 client proteins which play important roles in the regulation of survival and invasiveness in cancer cells. In addition, compounds 20 and 26 induce acetylation of α-tubulin and histone H3. Significantly, compounds 20 and 26 could effectively reduce programmed death-ligand 1 (PD-L1) expression in IFN-γ treated lung H1975 cells in a dose dependent manner. These findings suggest that dual inhibition of HDAC and HSP90 that can modulate immunosuppressive ability of tumor area may provide a better therapeutic strategy for cancer treatment in the future.",
keywords = "Design multiple ligand, Dual inhibitors, Heat shock protein, Histone deacetylase inhibitors, Lung cancer, Programmed death-ligand 1 (PD-L1)",
author = "Samir Mehndiratta and Lin, {Mei Hsiang} and Wu, {Yi Wen} and Chen, {Chun Han} and Wu, {Tung Yun} and Chuang, {Kuo Hsiang} and Chao, {Min Wu} and Chen, {Yi Ying} and Pan, {Shiow Lin} and Chen, {Mei Chuan} and Liou, {Jing Ping}",
note = "Copyright {\circledC} 2019. Published by Elsevier Masson SAS.",
year = "2020",
month = "1",
day = "1",
doi = "10.1016/j.ejmech.2019.111725",
language = "English",
volume = "185",
pages = "111725",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier Masson SAS",

}

TY - JOUR

T1 - N-alkyl-hydroxybenzoyl anilide hydroxamates as dual inhibitors of HDAC and HSP90, downregulating IFN-γ induced PD-L1 expression

AU - Mehndiratta, Samir

AU - Lin, Mei Hsiang

AU - Wu, Yi Wen

AU - Chen, Chun Han

AU - Wu, Tung Yun

AU - Chuang, Kuo Hsiang

AU - Chao, Min Wu

AU - Chen, Yi Ying

AU - Pan, Shiow Lin

AU - Chen, Mei Chuan

AU - Liou, Jing Ping

N1 - Copyright © 2019. Published by Elsevier Masson SAS.

PY - 2020/1/1

Y1 - 2020/1/1

N2 - Novel dual inhibitors of histone deacetylase (HDAC) and heat-shock protein 90 (HSP90) are synthesized and evaluated. These compounds are endowed with potent HDAC and HSP90 inhibitory activities with IC50 values in nanomolar range with Compound 20 (HDAC IC50 = 194 nM; HSP90α IC50 = 153 nM) and compound 26 (HDAC IC50 = 360 nM; HSP90α IC50 = 77 nM) displaying most potent HDAC and HSP90α inhibitory activities. Both of these compounds induce HSP70 expression and down regulate HSP90 client proteins which play important roles in the regulation of survival and invasiveness in cancer cells. In addition, compounds 20 and 26 induce acetylation of α-tubulin and histone H3. Significantly, compounds 20 and 26 could effectively reduce programmed death-ligand 1 (PD-L1) expression in IFN-γ treated lung H1975 cells in a dose dependent manner. These findings suggest that dual inhibition of HDAC and HSP90 that can modulate immunosuppressive ability of tumor area may provide a better therapeutic strategy for cancer treatment in the future.

AB - Novel dual inhibitors of histone deacetylase (HDAC) and heat-shock protein 90 (HSP90) are synthesized and evaluated. These compounds are endowed with potent HDAC and HSP90 inhibitory activities with IC50 values in nanomolar range with Compound 20 (HDAC IC50 = 194 nM; HSP90α IC50 = 153 nM) and compound 26 (HDAC IC50 = 360 nM; HSP90α IC50 = 77 nM) displaying most potent HDAC and HSP90α inhibitory activities. Both of these compounds induce HSP70 expression and down regulate HSP90 client proteins which play important roles in the regulation of survival and invasiveness in cancer cells. In addition, compounds 20 and 26 induce acetylation of α-tubulin and histone H3. Significantly, compounds 20 and 26 could effectively reduce programmed death-ligand 1 (PD-L1) expression in IFN-γ treated lung H1975 cells in a dose dependent manner. These findings suggest that dual inhibition of HDAC and HSP90 that can modulate immunosuppressive ability of tumor area may provide a better therapeutic strategy for cancer treatment in the future.

KW - Design multiple ligand

KW - Dual inhibitors

KW - Heat shock protein

KW - Histone deacetylase inhibitors

KW - Lung cancer

KW - Programmed death-ligand 1 (PD-L1)

UR - http://www.scopus.com/inward/record.url?scp=85073748510&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85073748510&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2019.111725

DO - 10.1016/j.ejmech.2019.111725

M3 - Article

C2 - 31655430

AN - SCOPUS:85073748510

VL - 185

SP - 111725

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

M1 - 111725

ER -