作者: Tang, Sijia ; Nijampatnam, Bhavitavya ; Luo, Ming ; Velu, Sadanandan E. ; Yin, Jun ; Terrell, James Ross ; Wang, Wei ; Zhang, Ruiwen ; Jeong, In Ho ; Faniyi, Oluwafoyinsola Omobodunde

AbstractMouse double minute 2 homolog (MDM2) is an E3 ubiquitin‐protein ligase that is involved in the transfer of ubiquitin to p53 and other protein substrates. The expression of MDM2 is elevated in cancer cells and inhibitors of MDM2 showed potent anticancer activities. Many inhibitors target the p53 binding domain of MDM2. However, inhibitors such as Inulanolide A and MA242 are found to bind the RING domain of MDM2 to block ubiquitin transfer. In this report, crystal structures of MDM2 RING domain in complex with Inulanolide A and MA242 were solved. These inhibitors primarily bind in a hydrophobic site centered at the sidechain of Tyr489 at the C‐terminus of MDM2 RING domain. The C‐terminus of MDM2 RING domain, especially residue Tyr489, is required for ubiquitin discharge induced by MDM2. The binding of these inhibitors at Tyr489 may interrupt interactions between the MDM2 RING domain and the E2‐Ubiquitin complex to inhibit ubiquitin transfer, regardless of what the substrate is. Our results suggest a new mechanism of inhibition of MDM2 E3 activity for a broad spectrum of substrates.

2019-09-01·Cancer Letters1区 · 医学

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

1区 · 医学

Article

作者: Nijampatnam, Bhavitavya ; Zhang, Ruiwen ; Wang, Wei ; Hu, Bo ; Li, Xin ; Fan, Jia ; Cheng, Jian-Wen ; Yang, Xin-Rong ; Qin, Jiang-Jiang ; Velu, Sadanandan E

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.

2018-10-01·Cancer Research1区 · 医学

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

1区 · 医学

Article

作者: Wang, Wei ; Hu, Ming ; Zhang, Ruiwen ; Qin, Jiang-Jiang ; Ruan, Ke-He ; Velu, Sadanandan E. ; Zhou, Jianwei ; Voruganti, Sukesh ; Nijampatnam, Bhavitavya

AbstractOverexpression 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.

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