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MDM2-NFAT1 dual inhibitor, MA242: Effective against hepatocellular carcinoma, independent of p53.

Abstract：

:The overexpression of the MDM2 oncoprotein frequently occurs in hepatocellular carcinoma (HCC). Small molecules that inhibit MDM2-p53 binding show efficacy against p53 wild-type HCC, but most patients have p53-mutant tumors and intrinsic resistance to such MDM2 inhibitors. We have recently discovered that the NFAT1 transcription factor upregulates MDM2 expression, but the role of NFAT1 in HCC is not fully understood. The present study was designed to develop a dual-targeting (MDM2 and NFAT1) strategy for the treatment of HCC. We herein demonstrate that high expression levels of NFAT1 and MDM2 are independent predictors of a poor prognosis in patients with HCC. We have also identified a MDM2 and NFAT1 dual inhibitor (termed MA242) that induces MDM2 auto-ubiquitination and degradation and represses NFAT1-mediated MDM2 transcription. MA242 profoundly inhibits the growth and metastasis of HCC cells in vitro and in vivo, independent of p53. The present efficacy and mechanistic studies provide proof-of-principle data to support the therapeutic value of this dual targeting strategy in future drug discovery.

journal_name

Cancer Lett

journal_title

Cancer letters

authors

Wang W,Cheng JW,Qin JJ,Hu B,Li X,Nijampatnam B,Velu SE,Fan J,Yang XR,Zhang R

doi

10.1016/j.canlet.2019.114429

subject

Has Abstract

pub_date

2019-09-10 00:00:00

pages

156-167

eissn

0304-3835

issn

1872-7980

pii

S0304-3835(19)30351-9

journal_volume

459

pub_type

杂志文章

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