Innovative targets for circadian drug discovery: REV-ERBalpha and RORalpha

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Humans are rhythmic beings, with daily sleep/wake cycles affecting almost every aspect of physiology and behaviour. Our master circadian clock is known to reside in the suprachiasmatic nuclei (SCN) of the hypothalamus. Via multiple pathways, output from the SCN synchronizes peripheral oscillators throughout the body. The discovery of the molecular components of the core clock has provided new insight into the link between circadian biology and chronic diseases, but has not been exploited for drug discovery. With this work we will prepare chemical probes for the clock proteins REV-ERBalpha and RORalpha, characterise their activity in models of inflammation, and deliver lead optimised molecules for clinical development.