Potent anti-inflammatory activity of a novel of class Hsp90 inhibitors for multiple sclerosis (51.1)

Abstract

Abstract Current therapies for multiple sclerosis (MS) generally reduce the frequency, severity and duration of relapses, and may slow disease progression, but are not curative. Clinical benefit also comes with side effects that range from mild to life-threatening. Heat shock protein 90 (Hsp90) is a molecular chaperone required for the stability and function of many proteins that modulate cellular response to environmental stresses. Due to its central role in multiple immune-mediated mechanisms, Hsp90 has recently emerged as a potential target for MS therapy. A number of the inflammatory mediators underlying MS are known Hsp90 client proteins, and Hsp90 blockade represents an attractive multi-targeted therapeutic approach given its alternative mechanisms of neuroprotection and inhibition of inflammation. Here we describe a novel class of small molecule inhibitors that preferentially target Hsp90 associated with immune-mediated pathways and which demonstrate potent inhibitory activity, high oral bioavailability and prolonged CNS exposure. Further, the lead compound displays broad activity in a number of relevant in vitro and in vivo models; including inhibition of cytokine production by human PBMCs, decreased nitric oxide production by primary rat astrocytes, and efficacy in an adoptive transfer model of MS. Taken together, this class of Hsp90 inhibitors may potentially provide new avenues to counter immune overstimulation in MS patients.