Introduction to the Therapeutic Platform of cPLA2α inhibition
The inflammatory pathway is a complex and intricate system that controls the regulation and activation of several genes and their products. cPLA2α plays a role in the production of arachidonic acid, a substrate for several important enzymes in the induction pathway of inflammatory responses. cPLA2α hyperactivity plays a defining role in chronic inflammatory disorders.
The inflammatory pathway is initiated by external cytokines attaching to cytokine receptors, initiating a signaling cascade with several MAP kinases. This leads to activation of NIK, which releases NFκB from a complex consisting of IKK and NFκB, thus activating NFκB and leading to the degradation of IKK. The release of NFκB makes it available to be transported into the nucleus, where it initiates transcription of several inflammatory related genes. The activation of these results in many inflammatory symptoms.
In addition to this cascade, upon binding of the cytokine to its receptor a membrane lipid shuffling is happening, triggering a secretory PLA2 (sPLA2) activity resulting in a minute release of arachidonic acid, an inflammatory signaling molecule, into the cytoplasma. Arachidonic acid is then a substrate to several inflammatory pathway enzymes, represented by COX1, COX2, and LOX (cyclooxygenases and lipoxygenases), which transforms this small amount of arachidonic acid into signaling molecules called eicosanoids. These are then transported through the cell membrane, where they either can have an endocrine effect or a local effect upon itself.
This initially small amount of eicosanoids attach locally to the GPCRs, starting a cell cascade signaling pathway via PI3 kinase and Protein kinase C by phosphorylation. Our intervention point is the cPLA2α enzyme that becomes phosphorylated by MAP p38 kinase. cPLA2α transforms phospholipids from inner cell membranes to arachidonic acid, that, as previously described, is transformed to eicosanoids by COX1/COX2 and LOX. Now we have a loop that repeatedly will stimulate the G-protein coupled cascade, thus producing higher and higher amounts of the pathway substrates, fueling the activity of the enzymes involved in the loop.
In this loop, one of the cascade signaling proteins, the MAP p38 kinase is also an important kinase in the NFκB signalling pathway. Without its activity, the NFκB signalling pathway is halted. Limiting the activity of the MAP p38 kinase by inhibiting the eicosanoid loop will in turn also limit the NFκB signalling pathway for inflammatory responses.
In chronic inflammatory diseases a key activity observed is high amounts of arachidonic acid due to a hyperactive cPLA2α. An inhibition of cPLA2α will thus lower the input to arachidonic acid dependent enzymes producing the eicosanoids stimulating further inflammatory activity. A basal level of COX/LOX activity and of eicosanoids necessary to maintain household properties as in normal cells will then be achieved.
Drug discovery pipeline and development projects
Avexxin has several molecules in the pipeline at different developmental stages. The newest molecules were added to the portfolio in 2015.
With our lead compound – AVX001 – we are developing a novel therapy for the treatment of psoriasis and other skin conditions. The mechanism based, rationally designed, lead compound is a potent inhibitor of TNFa induced inflammation in keratinocytes, and a potent candidate for a powerful anti-psoriatic drug.
Selected research papers on inflammatory mechanisms by Prof. Berit Johansen:
- Omland, S. H., Habicht, A., Damsbo, P., Wilms, J., Johansen, B. & Gniadecki, R. 2017. A randomized, double-blind, placebo-controlled, dose-escalation first-in-man study (phase 0) to assess the safety and efficacy of topical cytosolic phospholipase A2 inhibitor, AVX001, in patients with mild to moderate plaque psoriasis. J Eur Acad Dermatol Venereol, 31, 1161-1167. (Read article)
- Kim, E., H. M. Tunset, J. Cebulla, R. Vettukattil, H. Helgesen, A. J. Feuerherm, O. Engebråten, G. M. Mælandsmo, B. Johansen and S. A. Moestue (2016). Anti-vascular effects of the cytosolic phospholipase A2 inhibitor AVX235 in a patient-derived basal-like breast cancer model. BMC Cancer 16(1): 1-11 (Read article)
- Sommerfelt, R. M., Feuerherm, A. J., Skuland, T., & Johansen, B. (2015). Cytosolic Phospholipase A2 Modulates TLR2 Signaling in Synoviocytes. PLoS ONE, 10(4), e0119088. (Read article)
- Kokotos G, Feuerherm AJ, Barbayianni E, Shah I, Sæther M, Magrioti V, Nguyen T, Constantinou-Kokotou V, Dennis EA, Johansen B. Inhibition of Group IVA Cytosolic Phospholipase A2 by Thiazolyl Ketones in Vitro, ex Vivo and in Vivo. J. Med. Chem. 2014 Sep 25;57(18):7523-35. (Read article)
A more extensive list can be found here: List of Publications in Scientific Journals