Discovery and Characterization of Dual Inhibitors of MDM2 and NFAT1 for Pancreatic Cancer Therapy.

Abstract

Overexpression and activation of the murine double minute 2 (MDM2) or nuclear factor of activated T cells 1 (NFAT1) oncoproteins frequently occur in pancreatic cancer. Most MDM2 inhibitors under development target MDM2-p53 binding and have little or no effect on cancers without functional p53, including pancreatic cancer. Some available compounds indirectly inhibit NFAT1 activity by interfering with calcineurin activity, but there are currently no specific inhibitors against NFAT1. Here we performed a high-throughput virtual and cell-based screening to yield a lead compound (MA242) that can directly bind both MDM2 and NFAT1 with high affinity, induce their protein degradation, and inhibit NFAT1-mediated transcription of MDM2 As a result of this binding, MA242 decreased cell proliferation and induced apoptosis in pancreatic cancer cell lines regardless of p53 status. MA242 alone or in combination with gemcitabine inhibited pancreatic tumor growth and metastasis without any host toxicity. Our data indicate that targeting both MDM2 and NFAT1 represents a novel and effective strategy to treat pancreatic cancer.Significance: These findings suggest that pharmacological inhibition of both MDM2 and NFAT1 is a promising strategy for the treatment of pancreatic cancer, even in tumors lacking functional p53. Cancer Res; 78(19); 5656-67. ©2018 AACR.

• Authors: Wei Wang, Jiang-Jiang Qin, Sukesh Voruganti, Bhavitavya Nijampatnam, Sadanandan E Velu, Ke-He Ruan, Ming Hu, Jianwei Zhou, Ruiwen Zhang
• Journal: Cancer research (Cancer Res) Vol. 78 Issue 19 Pg. 5656-5667 (10 01 2018) ISSN: 1538-7445 [Electronic] United States
• PMID: 30217928 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Heterocyclic Compounds, 3-Ring
• MA242
• NFATC Transcription Factors
• NFATC2 protein, human
• RNA, Small Interfering
• TP53 protein, human
• Tumor Suppressor Protein p53
• Deoxycytidine
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2
• Calcineurin
• Gemcitabine

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Calcineurin (metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Deoxycytidine (analogs & derivatives, pharmacology)
• Drug Discovery
• Drug Screening Assays, Antitumor
• Female
• Gene Expression Regulation, Neoplastic
• Heterocyclic Compounds, 3-Ring (pharmacology)
• Mice
• Mice, Nude
• NFATC Transcription Factors (antagonists & inhibitors)
• Neoplasm Transplantation
• Pancreatic Neoplasms (drug therapy, metabolism)
• Protein Binding
• Proto-Oncogene Proteins c-mdm2 (antagonists & inhibitors)
• RNA, Small Interfering (metabolism)
• Tumor Suppressor Protein p53 (metabolism)
• Gemcitabine