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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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.
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