Program

Casein Kinase 1 delta/epsilon inhibitors: A new class of anti-asthma agents?

[Speaker] Alastair G. Stewart:1
[Co-author] Christine R Keenan:1,2, Meina Li:1, Connie Xia:1
1:Department of Pharmacology and Therapeutics, University of Melbourne, Australia, 2:Walter Eliza hall Institute, Australia

Asthma affects more than 10% of the population. Severe steroid-dependent asthma occurs in ~5% of patients but is estimated to account for 50% of the cost. The only mechanistically new therapies for asthma in the past 30 years, target so-called T2 asthma, which is driven by T helper 2 -type cytokines, with antibodies targeting interleukin-5 or its receptor. These biological therapies do not meet the needs of the majority of the severe steroid dependent asthma subgroup. Our efforts have been directed to identifying pathways which underlie the remodelling response, which is prominent in severe asthma. This focus on structural cell types within the airway wall has identified that the mechanical microenvironment impacts on the pharmacology of the airway, a phenomenon more generally referred to as mechanopharmacology (Krishnan et al, 2016). Recent work has identified casein kinase 1delta /epsilon (CK1 delta/epsilon) as a downstream effector of the remodelling and steroid resistance inducing effects of transforming growth factor (Xia et al 2017). This CK1 delta/epsilon pathway is also implicated in regulating the circadian clock "signalling circuit" via phosphorylation of CLOCK repressors, period and cryptochrome. The connection of CK1delta /epsilon to glucocorticoid activity holds the potential to explain the well-known connection between circadian rhythm and severity of allergy and asthma symptoms, that are more pronounced in the early morning. In addition, there is evidence of anti-allergic effects of CK1 delta/epsilon inhibitors that occur independently of actions on glucocorticoids. We are now examining the clinical development potential of the CK1 delta/epsilon inhibitors in treatment of severe asthma and data on the prototypical inhibitor, PF670462 and on novel agents will be presented.

Krishnan, R., Park, J-A., Seow, C.Y., Lee, P.V.S., Stewart, A.G. (2016). Cellular biomechanics in drug screening and evaluation: Mechanopharmacology. Trends in Pharmacological Sciences 37:87-100.
Xia, Y.C., Radwan, A., Keenan, C.R., Langenbach, S.Y. Li, M Radojicic, D., Londrigan, S.L, Gualano, R.C., Stewart, A.G. (2017). Glucocorticoid insensitivity in virally infected airway epithelial cells is dependent on transforming growth factor-beta activity. PLOS Pathogens http://dx.doi.org/10.1371/journal.ppat.1006138


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