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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.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Mehndiratta S,Lin MH,Wu YW,Chen CH,Wu TY,Chuang KH,Chao MW,Chen YY,Pan SL,Chen MC,Liou JP

doi

10.1016/j.ejmech.2019.111725

subject

Has Abstract

pub_date

2020-01-01 00:00:00

pages

111725

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(19)30877-3

journal_volume

185

pub_type

杂志文章

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