Blue Oak integrates in vivo phenotypic assays, a unique chemistry platform and high-content data analysis to find the next generation of drugs to treat brain disorders.
Brain disorders: the largest medical and economic burden of any chronic illness
Current treatment options are relatively ineffective and can have significant adverse effects. It’s frustrating for patients and physicians that few new drug classes have been launched in the past quarter century and that large pharma has reduced internal R+D efforts. Clearly, new drugs are needed.
It’s time for a new approach to drug discovery: An unbiased, systems-based approach delivers better clinical candidates
We now recognize that a highly “reductionist” approach of drugging individual molecular targets – the dominant large pharma strategy for the past quarter century – fails to produce drugs with new modes-of-action.
Genomics, optogenetics and stem cell technology hold promise, but many years may be needed to translate these data into new drugs.
A “functionalist” strategy using in vivo assays is particularly effective for finding first-in-class drugs and new modes-of-action. In fact, this strategy yielded many of the CNS drug classes still in use today. The Blue Oak founders have extensive experience using this concept to discover and optimize drugs for brain disorders that are safe, structurally and pharmacologically novel and have confirmed activity in human clinical studies.
Mental illness results from dysregulated brain circuits controlling specific aspects of behavior. In vivo phenotypic assays preserve these emergent properties and measure physiologically relevant compound effects. At the systems level, knowledge of the molecular target is not required and chemistry optimization can be effectively driven by measuring complex physiological endpoints.
This allows Blue Oak to identify molecules having polypharmacology that are distinct from current drug classes. Importantly, optimized leads using a phenotypic approach are both first-in-class experimental drugs and pharmacological tools for identifying novel disease pathways.
ADEPtTM chemistry platform: Designed for CNS activity
Blue Oak accelerates the drug discovery with our proprietary chemistry platform, ADEPtTM (Adaptive Design Engineering for Privileged Structures) that rationally designs privileged chemotypes with CNS activity. Initial filters select structures that have physicochemical properties correlated with phenotypic activity. Subsequent design elements incorporate structural features commonly found in complex biological systems. The result are privileged chemotypes that are structurally novel, drug-like and easily optimizable.
An important benefit of this design process is that the Blue Oak library occupies a substantially different region of chemistry space than much larger corporate compound collections. Modern corporate libraries contain small, densely populated regions of chemical space that bind to a specific target or family of genetically related targets.
In contrast, ADEPtTM selects for molecules that reside in scarcely populated, but biologically relevant, regions of chemistry space. Since our compounds have not been extensively screened by other companies, Blue Oak exploits a unique patent space.
Systems neurobiology: Rapid optimization of clinical leads
Blue Oak partners with companies that have validated in vivo assays that are robust, reproducible and data-rich. Our first programs use PsychoGenics’ SmartCubeâ technology to generate deep behavioral profiles as a surrogate indicator of brain circuit activity. Therapeutic potential is predicted by behavioral similarity to reference drug classes. A key advantage is the rapid discovery and optimization of active compounds having superior brain exposure and ADME properties. Compounds that engage mechanistically appropriate neurotransmitter systems, brain regions and circuits are then advanced into the clinic.
Translational medicine biomarkers: Early clinical validation
Phase 1 clinical confirmation of therapeutic potential relies on phEEG and phMRI as translational medicine imaging biomarkers of patient brain and circuit activity. These clinical candidates will help inform emerging public data from genomics, optogenetics and stem cell approaches to identify cellular pathways and novel targets. Our lead programs aim to treat important brain disorders with new drugs that have modes-of-action distinct from existing drug classes.