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

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

  • Cancer Lett. 2019 Sep 10;459:156-167. doi: 10.1016/j.canlet.2019.114429.
Wei Wang 1,  Jian-Wen Cheng 2,  Jiang-Jiang Qin 3,  Bo Hu 2,  Xin Li 3,  Bhavitavya Nijampatnam 4,  Sadanandan E Velu 4,  Jia Fan 5,  Xin-Rong Yang 6,  Ruiwen Zhang 7
Affiliations

Affiliations

  • 1 Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, 77204, USA; Drug Discovery Institute, University of Houston, Houston, TX, 77204, USA. Electronic address: wwang4@central.uh.edu.
  • 2 Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 3 Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, 77204, USA.
  • 4 Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
  • 5 Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 6 Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address: yang.xinrong@zs-hospital.sh.cn.
  • 7 Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, 77204, USA; Drug Discovery Institute, University of Houston, Houston, TX, 77204, USA. Electronic address: rzhang27@central.uh.edu.
PMID: 31181320 DOI: 10.1016/j.canlet.2019.114429
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.

Keywords

CRISPR/Cas9; Hepatocellular carcinoma; MDM2; Metastasis; NFAT1; Patient-derived xenograft.

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