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Methionine aminopeptidase type II (MetAP2) — an enzyme in the metalloprotease class found in virtually all cells — is the target for SynDevRx’s novel fumagillin-derived polymer-drug conjugates.

MetAP2 removes the initiator methionine residue from newly-formed proteins (Lowther 2000). Methionine removal is required for subsequent post-translational modification of key substrates (Turk 1999) (Warder 2008) that regulate many cellular processes, including:

  • Hypoxic response
  • Angiogenesis (the development of new blood vessels) (Ingber 1990)
  • Cell proliferation (Yeh 2000) (Tucker 2008)
  • Turnover of specific proteins (Sundberg 2011)

Why Target MetAP2?

Independent academic and clinical research has implicated MetAP2 as a key mediator in diseases related to hypoxia, angiogenesis and chronic inflammation, including:

  • Many types of cancer (Selvakumar 2006)
  • Morbid obesity (Joharapurkar 2014)
  • Rheumatoid arthritis (Brahn 2009)
  • Eye diseases (e.g. age-related macular degeneration) (Yoshimura 2013)

In 1997, MetAP2 was identified as the cellular target of fumagillin-class molecules (Griffith 1997) (Sin 1997). At SynDevRx, we’ve designed our lead compound to apply the combined, clinically-established beneficial effects of MetAP2 inhibition — anti-tumor, anti-metabolic and anti-angiogenic — while avoiding the safety challenges typical of small-molecule fumagillin derivatives.

Cancer

MetAP2 has been shown to be upregulated in many cancers compared with normal tissues (Tucker 2008). Clinical studies of small-molecule fumagillin derivatives have demonstrated anti-tumor activity, though toxicity challenges (particularly neurotoxicity) prevented further development of these compounds (Tran 2004) (Kudelka 1998) (Bhargava 1999).

Metabolic Dysfunction

Metabolic dysfunction (which is typical in overweight and obese people) has been shown to predispose people to get certain types of cancer (Lohmann 2016), and cancer patients who are overweight or obese have higher cancer mortality rates than their metabolically normal counterparts (Calle 2003) (LaubySecretan 2016). MetAP2 inhibition has been clinically shown to decrease production of key metabolic factors known to stimulate cancer cell proliferation and metastasis.

Angiogenesis

MetAP2 has been shown to play a key role in angiogenesis, which tumors need to grow and spread. Inhibition of angiogenesis is a validated strategy for the treatment of cancer. For example, drugs such as bevacizumab (Avastin®), aflibercept (Zaltrap®) and ramucirumab (Cyramza ®) target angiogenesis by interfering with vascular endothelial growth factor (VEGF) signaling. The fungal metabolite fumagillin and its structural analogs have also been shown to exert anti-angiogenic effects through the selective and irreversible inhibition of MetAP2 (Satchi-Fainaro 2004) (Zhang 2000).