Seminario: Fenoterol, from asthma to brain cancer and beyond
Fenoterol, from asthma to brain cancer and beyond: An adventure in drug repositioning and drug discovery
Dipartimento di Scienze per la Qualità della Vita
Chief Scientific Officer, Mitchell Woods Pharmaceuticals
Adjunct Professor Department of Oncology, McGill University
Adjunct Professor Department of Anesthesiology, Cooper Medical School
(R,R’;S,S’)-fenoterol is a b2-adrenergic receptor (b2-AR) agonist used in the treatment of asthma. We have recently demonstrated that (R,R’)-fenoterol increases contractility in a rat cardiomyocyte model and this isomer is being developed for use in congestive heart failure. Data from a screen of (R,R’)-fenoterol activity in b2-AR-expressing cell lines indicated that this compound also inhibits the proliferation of brain tumor melanoma cell lines and that this effect is mediated by activation of the b2-AR. This observation lead to the synthesis of (R,R’)-fenoterol analogs with the objective of increasing selectivity, potency and blood-brain barrier penetration. (R,R’)-4’-methoxy-1-naphthylfenoterol (MNF) is one of the products of the medicinal chemistry program that meets all of these objectives. MNF is active in b2-AR-expressing cancer cells, and is also active in cancer cells that do not predominately express b2-AR. This effect has been linked to MNF inhibition of the G-protein coupled receptor GPR55. Thus, MNF is a biotopic anticancer agent that acts as an agonist at b2-AR and as an antagonist at GPR55. The molecular, pharmacological and clinical effects of these properties will be discussed.