Methionine Aminopeptidase 2 Inhibitors in Cancer and Metabolic Disorders

Methionine aminopeptidase 2 (MetAP2) is a zinc-dependent metalloprotease that catalyses the cotranslational removal of N-terminal methionine from nascent polypeptides. Beyond its canonical role in protein maturation, MetAP2 regulates endothelial and lymphatic cell proliferation, lipid metabolism and energy homeostasis. In cancer, heightened MetAP2 activity supports angiogenesis, lymphangiogenesis and tumour growth by promoting endothelial cell invasion and vessel remodelling. In metabolic disorders, MetAP2 modulates adipose tissue function, enhancing energy expenditure through direct action on brown adipocytes and regulation of β-adrenergic signalling. Small-molecule inhibitors of MetAP2—ranging from natural products (fumagillin and its analogues) to synthetic scaffolds (indazole and pyrazolo[4,3-b]indole derivatives)—have demonstrated potent anti-angiogenic and anti-obesity effects in preclinical models. Early clinical investigations have confirmed target engagement and manageable safety profiles, albeit with challenges in selectivity and dose-limiting toxicities. The dual relevance of MetAP2 in oncological and metabolic contexts offers a unique therapeutic axis, prompting the design of next-generation inhibitors that exploit both active-site and cryptic allosteric pockets to enhance specificity, reduce resistance and improve translational outcomes.

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Methionine Aminopeptidase 2 Inhibitors in Cancer and Metabolic Disorders publication trend

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Technical terms

Methionine aminopeptidase 2 (MetAP2): A metalloprotease that cleaves N-terminal methionine from nascent proteins and regulates angiogenesis and metabolism.

Angiogenesis: Formation of new blood vessels from pre-existing vasculature, critical for tumour growth and metastasis.

Lymphangiogenesis: Development of new lymphatic vessels, facilitating tumour cell dissemination.

Cryptic pocket: A transient, hidden binding site revealed by protein dynamics, exploitable for allosteric inhibitor design.

β-adrenergic signalling: A pathway triggered by catecholamines that regulates lipolysis and energy expenditure in adipose tissue.

Phase I dose-escalation study: A clinical trial to assess safety, tolerability and pharmacokinetics of a new drug in humans.

References

1. MetAP2 as a Therapeutic Target for Obesity and Type 2 Diabetes: Structural Insights, Mechanistic Roles, and Inhibitor Development. Biomolecules (2024).
2. Identification of a Cryptic Pocket in Methionine Aminopeptidase-II Using Adaptive Bandit Molecular Dynamics Simulations and Markov State Models. ACS Omega (2024).
3. The Role of Methionine Aminopeptidase 2 in Lymphangiogenesis. International Journal of Molecular Sciences (2020).
4. A First-in-Human, Dose Escalation Study of the Methionine Aminopeptidase 2 Inhibitor M8891 in Patients with Advanced Solid Tumors. Cancer Research Communications (2023).
5. MetAP2 inhibition increases energy expenditure through direct action on brown adipocytes. Journal of Biological Chemistry (2019).