2. Academic Validation
  3. The Novel MDM4 Inhibitor CEP-1347 Activates the p53 Pathway and Blocks Malignant Meningioma Growth In Vitro and In Vivo

The Novel MDM4 Inhibitor CEP-1347 Activates the p53 Pathway and Blocks Malignant Meningioma Growth In Vitro and In Vivo

  • Biomedicines. 2023 Jul 12;11(7):1967. doi: 10.3390/biomedicines11071967.
Yuta Mitobe 1 2,  Shuhei Suzuki 1 3,  Yurika Nakagawa-Saito 1,  Keita Togashi 1 4,  Asuka Sugai 1,  Yukihiko Sonoda 2,  Chifumi Kitanaka 1 5,  Masashi Okada 1
Affiliations

Affiliations

  • 1 Department of Molecular Cancer Science, School of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan.
  • 2 Department of Neurosurgery, School of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan.
  • 3 Department of Clinical Oncology, School of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan.
  • 4 Department of Ophthalmology and Visual Sciences, School of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan.
  • 5 Research Institute for Promotion of Medical Sciences, Faculty of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan.
PMID: 37509605 DOI: 10.3390/biomedicines11071967
Abstract

A significant proportion of meningiomas are clinically aggressive, but there is currently no effective chemotherapy for meningiomas. An increasing number of studies have been conducted to develop targeted therapies, yet none have focused on the p53 pathway as a potential target. In this study, we aimed to determine the in vitro and in vivo effects of CEP-1347, a small-molecule inhibitor of MDM4 with known safety in humans. The effects of CEP-1347 and MDM4 knockdown on the p53 pathway in human meningioma cell lines with and without p53 mutation were examined by RT-PCR and Western blot analyses. The growth inhibitory effects of CEP-1347 were examined in vitro and in a mouse xenograft model of meningioma. In vitro, CEP-1347 at clinically relevant concentrations inhibited MDM4 expression, activated the p53 pathway in malignant meningioma cells with wild-type p53, and exhibited preferential growth inhibitory effects on cells expressing wild-type p53, which was mostly mimicked by MDM4 knockdown. CEP-1347 effectively inhibited the growth of malignant meningioma xenografts at a dose that was far lower than the maximum dose that could be safely given to humans. Our findings suggest targeting the p53 pathway with CEP-1347 represents a novel and viable approach to treating aggressive meningiomas.

Keywords

HDM4; HDMX; MDM2 antagonist; MDMX; brain tumor; drug repositioning; drug repurposing.

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