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Newly synthesized methionine aminopeptidase 2 inhibitor hinders tumor growth

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Abstract

Methionine aminopeptidase 2 (MetAp2) inhibition has been recognized as a promising approach for suppressing angiogenesis and cancer progression. Small molecule fumagillol derivatives with adamantane side groups were synthesized and evaluated for MetAp2 inhibition activity, and a lead molecule with superior abilities to inhibit the enzymatic activity of MetAp2 was identified. The compound, referred to as AD-3281, effectively suppressed proliferation of cancer and endothelial cells and impaired tube formation of endothelial cells in vitro. When administered systemically, AD-3281 was well tolerated and led to a significant suppression of human melanoma and mammary tumor xenografts grown in mice. The activity in vivo was associated with reduced angiogenesis and tumor proliferation as detected histologically. In order to develop a formulation that can solubilize AD-3281 with a minimal content of organic solvents, biodegradable nanoparticles comprised of poly-lactic-co-glycolic acid (PLGA) were fabricated and characterized. Compared with the free compound, AD-3281-loaded nanoparticles showed an advantageous cellular availability and uptake, leading to higher activity in cells and better transport in three-dimensional (3D) cultures. Taken together, we introduce a novel MetAp2 inhibitor with high anti-cancer activity and a stable nano-formulation with a high potential for future clinical translation.

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The authors confirm that the data supporting the findings of this study are available within the article and supplementary materials. Raw data are available from the corresponding author on request.

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Acknowledgements

The graphical abstract and illustrations were created using BioRender.

Funding

This study was supported by the Israel Foundation of Science (ISF) (No. 3011004240) and the Israel Ministry of Health (MOH) (grant agreement # 3011005737). The funders had no role in the study design, data collection and interpretation, or in the decision to submit the work for publication.

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Author notes

  1. Rawnaq Esa and Eliana Steinberg contributed equally to this work.

Authors and Affiliations

  1. Institute for Drug Research, School of Pharmacy, The Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Jerusalem, Israel

    Rawnaq Esa, Eliana Steinberg, Arie Dagan, Katerina Tischenko & Ofra Benny

  2. The Lautenberg Center for General and Tumor Immunology, The Hadassah Medical School, The Hebrew University of Jerusalem, 91120, Jerusalem, Israel

    Arie Dagan & Zhanna Yekhtin

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  1. Rawnaq Esa
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Contributions

Rawnaq Esa: data curation, investigation, validation and writing — original draft. Eliana Steinberg: formal analyses and writing — review and editing. Arie Dagan: design and synthesis of derivates. Zhanna Yekhtin: animal experiments. Katerina Tischenko: FACS experiments and analyses. Ofra Benny: conceptualization, supervision, funding acquisition, resources and writing — original draft and review and editing. All authors read and approved the final manuscript.

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Correspondence to Ofra Benny.

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All institutional and national guidelines for the care and use of laboratory animals were followed. This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Ethics Committee (21–16453-4).

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Esa, R., Steinberg, E., Dagan, A. et al. Newly synthesized methionine aminopeptidase 2 inhibitor hinders tumor growth. Drug Deliv. and Transl. Res. 13, 1170–1182 (2023). https://doi.org/10.1007/s13346-022-01187-6

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