SBIR-STTR Award

Alzheimer's disease (AD) is an immense national public health burden. It is the 6th leading cause of death in the US with over 5.7 million Americans suffering, and costs of over $275 billion in health care and related expenses. This patient population is expected to almost triple over the next 30 years. Despite this urgent need, there are currently no disease-modifying agents approved. Neuron loss is the only physiological phenomena that has been directly linked to the cognition loss in patients, and a major cause of this brain cell death is endoplasmic reticulum (ER) stress-induced apoptosis caused by disrupted intracellular Ca2+ homeostasis. By targeting correction of this altered Ca2+ state, Neurodon has developed a series of novel small molecule positive allosteric modulators (PAMs) of the major ER Ca2+ handling protein, sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). Our PAMs rescue brain cells in vitro and in vivo, and improve memory and cognition in the APP/PS1 double transgenic mouse model of AD. These results support SERCA activation as a target for the development of disease-modifying therapeutics for AD. The overall goal of Neurodon is the development of effective and orally available drugs to slow or halt AD progression. In this initial Phase 1 proposal we will partner with the chemistry expertise and facilities at Northwestern University to deliver advanced leads having potential for oral availability and improved efficacy. These goals will be accomplished by pursuing the following Aims: 1) Perform hit-to-lead and lead optimization on our novel series of SERCA2b PAMs to improve biological activity and physical properties. Using synthetic chemistry, structure-based drug design, and ADME profiling, we will optimize our novel series to improve efficacy and enable oral administration. 2) To characterize our synthesized SERCA PAMs in cellular and functional assays to assess their efficacy and prioritize development candidates. We have developed 2 complimentary assays to rapidly vet our newly synthesized leads for potential as drug development candidates. Ultimately, the results of these proposed Aims will be the delivery of drug molecules to be advanced to candidate-seeking development activities including efficacy and toxicological studies in Phase 2.

Project Terms:
Affect; Aging; Alzheimer's Disease; Alzheimer's disease model; American; Amyloid beta-Protein; analog; Animal Model; Apoptosis; Apoptotic; APP-PS1; base; Biological; Biological Assay; Brain; brain cell; burden of illness; Ca(2+)-Transporting ATPase; Calcium; Cause of Death; Cell Death; Cell Line; Cell model; Cell Survival; Cells; Chemicals; Chemistry; Cholinesterase Inhibitors; Clinical; Cognition; Consequentialism; cost; Crystallization; Cytoplasm; Data; Dementia; design; Development; Disease; Disease Progression; Dose; Drug Delivery Systems; Drug Design; drug development; Endoplasmic Reticulum; endoplasmic reticulum stress; Equilibrium; Goals; Healthcare; Hela Cells; Homeostasis; Human; Image; Impaired cognition; improved; In Vitro; in vivo; innovation; insight; Intervention; Lead; lead optimization; Link; Memantine; Memory; method development; Mission; Modeling; Monitor; mouse model; Nerve Degeneration; neuroblastoma cell; neuron loss; Neurotransmitters; novel; Oral; Oral Administration; Pathogenesis; Pathway interactions; patient population; Patients; Peptides; Pharmaceutical Preparations; Pharmacology; Phase; physical property; Physiological; Plasmids; positive allosteric modulator; prevent; Protein Isoforms; Proteins; Public Health; Pump; response; screening; Senile Plaques; sensor; Series; Small Business Technology Transfer Research; small molecule; Structure; Synthesis Chemistry; Testing; theories; Therapeutic; Toxicology; Transgenic Mice; United States National Institutes of Health; Universities; Work;

Neurodon LLC proposes to conduct lead optimization and candidate-seeking activities on a novel series of neuroprotective small molecules that shows efficacy in a transgenic model of Alzheimer’s disease (AD). AD is a leading cause of death in the United States, with some estimates ranking it as high as third behind cardiovascular disease and cancer. Despite the enormity of this national public health burden, the therapeutic options are very limited. The few approved therapies treat only symptoms, and there are no disease-modifying therapies approved. All of the recent clinical trials have failed or are not meeting efficacy endpoints. With this patient population set to almost triple over the next 30 years, there is a dire need for disease-modifying therapies. Neuron loss is the only physiological phenomena that has been directly linked to the cognition and memory loss in patients, and a major cause of brain cell death in AD is endoplasmic reticulum (ER) stress- induced apoptosis caused by intracellular Ca2+ dyshomeostasis. Neurodon’s patented, small molecule positive allosteric modulators (PAMs) of the major ER Ca2+ handling protein, sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), rescue brain cells in vitro and in vivo, improve memory and cognition in the APP/PS1 double transgenic mouse model of AD, and reduce ER stress markers in vivo, enabling biomarker-driven drug discovery and an improved probability of clinical success. Our Phase 1 research met the technical milestone of developing molecules with improved in vitro profiles when compared to our previous proof-of-concept compounds. We developed 5 new PAMs with improved efficacy in an in vitro Alzheimer’s model, sub- micromolar potencies in neuroprotection assays, and improved physicochemical properties. In this proposal, we will again partner with the medicinal chemistry expertise and facilities at Northwestern University. We have also added additional experts to the team in Alzheimer’s models, SERCA biology, and behavioral animal models. Our goal of identifying development molecules for Alzheimer’s disease will be accomplished by pursuing the following Aims: 1) Perform lead optimization of SERCA2b PAMs via iterative medicinal chemistry synthesis. 2) Perform in vitro profiling in neuroprotective and synaptoprotective assays to measure potency and efficacy of SERCA2b PAMs. 3) Perform candidate-seeking activities to identify SERCA2b PAMs with drug- like properties. 4) Perform essential in vivo characterization studies on lead SERCA PAMs in the APP/PS1 transgenic mouse model of AD. The results of these Aims will be the identification of candidate molecules to progress into IND-enabling studies at Neurodon.

Public Health Relevance Statement:
Alzheimer’s disease (AD) is a leading cause of death in the US with no approved therapeutics to slow or halt disease progression. This proposal aims to deliver development candidates via optimization of our novel, brain-penetrant, neuroprotective molecules that have shown efficacy in cellular and animal models of AD. Our previous Phase I research met its technical milestones by delivering molecules with improved potency and physical properties, and this proposal aims to further optimize these scaffolds to provide IND-ready scaffolds.

Project Terms:
Alzheimer's Disease; Alzheimer's disease model; Alzheimer’s disease biomarker; Animal Model; Apoptosis; Apoptotic; APP-PS1; Behavioral; Behavioral Model; Biological; Biological Assay; Biological Availability; Biology; biomarker-driven; Brain; brain cell; Ca(2+)-Transporting ATPase; candidate identification; Cardiovascular Diseases; Cause of Death; Cell Culture Techniques; Cell Death; Cell model; Cells; Chemicals; Chemistry; Cholinesterase Inhibitors; Clinic; Clinical; Clinical Trials; Cognition; Cognitive; Cytoplasm; Dementia; Development; Disease; Disease Progression; Dose; drug discovery; Endoplasmic Reticulum; endoplasmic reticulum stress; Equilibrium; flexibility; Goals; Grant; Hippocampus (Brain); improved; In Vitro; in vitro activity; in vitro Model; in vivo; insight; Intervention; Lead; lead candidate; lead optimization; Legal patent; Link; Malignant Neoplasms; Measures; Memantine; Memory; Memory Loss; mouse model; Mutagenicity Tests; Nerve Degeneration; neuron apoptosis; neuron loss; Neurons; neuroprotection; Neurotransmitters; novel; Oral; Pathogenesis; Pathway interactions; patient population; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; physical property; Physiological; positive allosteric modulator; preservation; prevent; Probability; programs; Property; Protein Isoforms; Proteins; Public Health; Pump; Research; response; Risk; scaffold; screening; Senile Plaques; Series; Short-Term Memory; Small Business Innovation Research Grant; Small Business Technology Transfer Research; small molecule; spatial memory; Structure; success; Symptoms; Synthesis Chemistry; Testing; Therapeutic; Transgenic Mice; transgenic model of alzheimer disease; United States; Universities; Work