Modulating

Circadian Rhythms

The circadian system synchronizes behavioral and physiological processes with the environmental cycles of light, activity, and nutrient status. Direct pharmacological modification of the molecular clock or clock-controlled systems that drive diurnal physiology will restore rhythms and mitigate disease pathology.

Circadian Clocks

A system of biological clocks controls the daily, or circadian, rhythms of the body – daily cycles of behavior and physiology. Circadian rhythms are produced by natural factors within the body, but they are affected by signals from the environment responsible for switching on and off genes that control an organism’s internal molecular clocks.

A “master clock” in the brain – a specific group of neurons in the suprachiasmatic nucleus (SCN) – coordinates all the body clocks so that they are in sync. Clocks located in tissues outside the brain are regulated by the SCN, but are also modulated by feeding and activity. The SCN and clocks throughout the body control a broad array of behaviors and physiological processes, including energy balance, sleep, appetite, blood pressure, and the breakdown, storage, and release of glucose (sugar).

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The Connection to Disease

Circadian dysfunction is involved in the pathologies of various diseases.  Circadian rhythms can influence sleep-wake cycles, hormone release, body temperature, and other important bodily functions. Research into the composition, function, and effects of molecular clocks has demonstrated that disruption of normal circadian rhythms is associated with many diseases, including central nervous system, cardiovascular, and metabolic disorders; immune system dysfunction; and cancer.  Chronic disruption of molecular clocks contributes to disease, while a variety of lifestyle behaviors and chronic disease states disrupt circadian function. These disruptions disconnect physiological needs from environmental cues.

A growing body of evidence suggests that disruption of normal circadian cycles plays an important role in type 2 diabetes, Cushing’s syndrome, high blood pressure, obesity, sleep apnea, cancer, inflammation, sleep and other central nervous system disorders, and metabolic syndrome (the occurrence of a defined group of risk factors that increase the risk of coronary artery disease, stroke, and type 2 diabetes).

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Our Technology Platform: Reset’s Novel Approach to Drug Discovery

Reset’s Clocks discovery platform, a cohesive group of cell- and tissue-based assays and in vivo animal models, enables the efficient characterization of compounds for their effects on circadian rhythms.

  • Cell-based phenotypic screening using circadian clock reporters
  • Pharmacological effects in isolated tissues using clock reporters
  • Target de-convolution
  • Phenotype or target-driven Medicinal Chemistry
  • Preclinical evaluation in most suitable therapeutic area
  • Clinical Evaluation

The proprietary platform is able to rapidly identify compounds that modulate the activity and function of molecular clocks. The platform integrates computer algorithms with cell, tissue, and animal models based on molecular components of the circadian system, as well as gene regulation assays. This integrated platform enables the evaluation and identification of key molecular clock characteristics. Importantly, the platform also provides a high-throughput system for identifying compounds that modulate molecular clock activity and enables the optimization of drug candidates based on their activity in tissue and animal models.

 

Through its lead program, Reset has validated the therapeutic relevance of the platform by coupling circadian-modifying activities of various chemotypes with physiological improvement in animal models of diabetes and Cushing’s syndrome. Multiple chemical series that modify the molecular clock or its outputs, including Cry modulators for diabetes and Cushing’s syndrome, have been generated by the platform and can be advanced across a broad range of therapeutic indications linked with circadian dysregulation.