Autism is a neurodevelopmental disorder characterized by abnormal social interaction, deficits in interpersonal communication, and repetitive stereotyped behaviors with a number of individually- occurring associated symptoms, including intellectual impairment, anxiety, seizures, hyperactivity, hyper- or hypo-responsiveness to sensory stimulation, sleep disruption, and gastrointestinal abnormalities. It is noteworthy that hyperactivity, impulsivity, and inattention-core features of attention deficit hyperactivity disorder (ADHD)-occur as associated symptoms in a high percentage (41-78%) of autistic individuals. As a complex, multi-symptom disorder, a large number of gene mutations (heritable and de novo) as well as environmental and epigenetic factors are likely involved in the expression of autism. Currently, there is no cure or satisfactory treatment for autism. New therapeutic agents that would effectively address specific features of the complex disorder would be of high significance and are urgently needed. Casein Kinase 1 (CK1) is a protein kinase target implicated in tau-related neurodegeneration in Alzheimer's disease, in disruption of sleep/wake cycles dictated by the circadian clock, and as a mediator of behavioral hyperactivity. Intra-Cellular Therapies Inc (ITI) is an early-stage pharmaceutical company with an established drug discovery platform and expertise in discovering small- molecule inhibitors for protein phosphodiesterases (PDE1) and protein kinases, like CK1. Our long-time collaborator, Dr. Marc Flajolet of Dr. Paul Greengard's laboratory at The Rockefeller University, has demonstrated that mice engineered to overexpress CK1delta (¿) in a forebrain-restricted, tetracycline- inducible manner (CK1¿OE mice) display behavioral hyperactivity and stereotyped behaviors reminiscent of neurodevelopmental disorders such as autism and ADHD. ITI has identified potent and selective CK1 inhibitors that are orally bio-available, drug-like agents that represent novel chemical entities. Here we propose a one-year Phase I SBIR project aimed at optimizing our current portfolio of patentable CK1 inhibitors, including compounds with nanomolar potency and excellent brain penetrance, to identify compounds able to significantly block behavioral hyperactivity/stereotypy in the CK1¿OE mouse model, in collaboration with Dr. Flajolet. Upon successful completion of this early discovery/optimization project, we propose to apply for further Phase II SBIR support to investigate the utility of CK1 inhibitors for addressing hyperactivity and other behavioral features of autism in relevant animal models. The overall goal of our program is to (1) identify CK1 inhibitors suitable for development as therapeutic agents and (2) to use these agents to investigate the suitability of CK1 inhibitors for addressing specific behavioral features of the complex, multi-symptom disorder known as autism.
Public Health Relevance Statement: Public Health Relevance: Gretchen L Casein Kinase 1 Inhibitors for Autism
Project narrative: Intra-Cellular Therapies, Inc. ("ITI") has a biotechnology platform that has led us to innovative pharmaceutical therapies for CNS disorders based on intracellular signaling. We propose to develop safe, brain-penetrant drugs targeting a molecular target in the brain (casein kinase 1) that, when overexpressed, affects intracellular signaling in the brain and results in behavioral hyperactivity. We believe that inhibition of the target activity will reduce behavioral hyperactivity common in autism. By optimizing our promising CK1 inhibitors we will identify and develop new drug leads as CNS drug candidates and novel treatments for autism.
Project Terms: Address; Affect; Alzheimer's Disease; Animal Model; Anxiety; Attention deficit hyperactivity disorder; Attenuated; Autistic Disorder; base; Behavioral; Biological Assay; Biotechnology; Brain; casein kinase I; Central Nervous System Diseases; Chemicals; circadian pacemaker; Collaborations; Complex; Confidential Information; Development; Disease; Doctor of Philosophy; drug candidate; drug discovery; Drug Targeting; Engineering; Epigenetic Process; gastrointestinal; Gene Mutation; Goals; Hyperactive behavior; Impairment; improved; Impulsivity; In Vitro; in vivo; inattention; Individual; inhibitor/antagonist; innovation; Laboratories; Lead; Mediator of activation protein; Molecular Target; Motor Activity; mouse model; Mus; Nerve Degeneration; Neurodevelopmental Disorder; novel; novel therapeutics; overexpression; Penetrance; Permeability; Personal Communication; Pharmaceutical Preparations; Pharmacologic Substance; Phase; phosphoric diester hydrolase; Phosphotransferases; Pilot Projects; Plasma; pre-clinical; programs; Prosencephalon; Protein Isoforms; Protein Kinase; Proteins; public health relevance; Research; Seizures; Sensory; Signal Transduction; Sleep; Sleep Wake Cycle; Small Business Innovation Research Grant; small molecule; Social Interaction; Staging; Stereotyped Behavior; stereotypy; Symptoms; tau Proteins; Testing; Tetracyclines; Therapeutic; Therapeutic Agents; Time; tool; trend; Universities; Wo
