We collaborate with world-renowned biologists and endeavor to transform their discoveries in neuroscience into opportunities for drug discovery. Brief descriptions of current medicinal chemistry projects and the respective academic biologist collaborator are outlined below:
In the hit-to-lead phase, preliminary SAR has been established, but a number of issues will be identified with the compounds that typically include: physicochemical (e.g., solubility, stability); pharmacokinetic (e.g., oral exposure, brain penetration); toxicity liabilities; and patentability. The goal is to further optimize and identify compounds with oral efficacy and safety in disease relevant models. Significant fine-tuning of properties may require intensive medicinal chemistry and compound evaluation before a clinical candidate can be identified.
Enhancing the expression of Klotho protein.
This is a novel approach to treat Alzheimer’s Disease (AD), Multiple Sclerosis (MS) and Chronic Kidney Disease (CKD). This project is in collaboration with Professor Carmela Abraham at Boston University and is aimed at modulating the cytoprotective, anti-aging protein Klotho. Klotho-deficient mice manifest a syndrome resembling accelerated human aging and show cognitive decline. By contrast, overexpression of Klotho in mice extends their average life span between 19% and 31% compared to normal mice. The Abraham group at BU originally discovered that Klotho is considerably decreased in the aged brains of monkeys, rats, and mice. Currently, the BU team is identifying Klotho receptors in the brain and investigating the signaling pathways by which Klotho exerts its protective effects on neurons and oligodendrocytes. In collaboration with Professor Abraham, the LDDN developed a high-throughput screen (HTS), and we identified compounds that enhance the expression of Klotho. Currently we are studying the effects of these compounds to therapeutically exploit these protective effects. Medicinal chemistry optimization is now in progress to improve potency, solubility, and pharmacokinetic properties.
Restoration of Glutamate Transporter Protein (EAAT2) for the treatment of Amyotrophic Lateral Sclerosis (ALS), AD, and PD.
Collaborator: Professor Glenn Lin at Ohio State University. The concentration of glutamate in the synaptic cleft is tightly regulated by the interplay between glutamate release and glutamate clearance. Abnormal glutamate release and/or dysfunction of glutamate clearance can cause over-stimulation of glutamate receptors and result in neuronal injury or death known as excitotoxicity. Excitotoxicity contributes to a number of acute and chronic neurodegenerative diseases. Blocking glutamate receptors and/or reducing glutamate release have been therapeutic strategies for the prevention of excitotoxicity; however, the benefits of these approaches are limited. We have targeted the glial glutamate transporter EAAT2, which is primarily localized in peri-synaptic processes of astrocytes closely associated with excitatory synaptic contacts, and which is responsible for maintaining low extracellular glutamate concentrations. Following a HTS, we identified small molecules that increase protein expression of EAAT2 providing neuroprotection. Importantly, we have performed efficacy studies using one of our compounds in several animal models of disease, including SOD1(G93A) mouse model of ALS. Significantly, the results show that this compound has profound protective effects in proof of concept disease models. Medicinal chemistry optimization is now in progress to fine tune drug-like properties and to identify compounds suitable for advanced pre-clinical studies.
Towards a treatment for Spinal Muscular Atrophy (SMA).
Our collaborator, Professor Elliot Androphy at Indiana University, is a world-renowned authority on SMA and originally discovered the role of exon 7 splicing in the SMA back-up gene SMN2. SMA is the leading heritable cause of infant mortality worldwide. It is a neurodegenerative disorder that presents as progressive muscle wasting and loss of motor function. SMA is an autosomal recessive disorder caused by deletion of the survival motor neuron gene 1 (SMN1). There is no cure or effective treatment for SMA, and drugs that improve motor function and life expectancy are desperately needed. We have discovered two distinct series of small molecules that increase SMN protein expression by two to three-fold and that are efficacious in two mouse models of SMA. Compounds produced an increase in brain and spinal cord levels of SMN protein and significant increases in life-span and motor function in both the D7 (severe) and 2B- (intermediate) mouse models of SMA. We recently discovered a new lead series that has good drug-like properties, including good oral pharmacokinetics and brain exposure. Optimization of this series is now in progress with the goal to identify a pre-clinical candidate for the treatment of SMA.
In the hit-to-lead phase, we take the hits from screening, optimize potency and drug-like properties to establish an SAR for the series, and identify compounds suitable for use as probes in in vivo proof of concept (POC) studies.
Inhibition of Superoxide Dismutase 1 (SOD-1) for the treatment of ALS.
Our collaborator, Professor Robert Brown at University of Massachusetts (UMASS) Medical School, is the leading authority in the field of ALS, who discovered the first ALS gene, superoxide dismutase (SOD1), in 1993, and the SOD1 mouse model of ALS in 1994. Dr. Brown has since played a central role in the discovery of other mutations or genetic variants in several ALS-related genes including alsin, dynactin, KIFAP3, and FUS/TLS. We have performed a HTS for compounds that suppress SOD1 expression in HEK-293 cells, and we have identified a number hits that were confirmed in a secondary qRTPCR assay, including a drug that is FDA approved for a different and peripheral indication. Unfortunately, this undisclosed drug does not have suitable brain penetration for use as a CNS drug. Medicinal chemistry optimization now is in progress with the objective of identifying potent compounds with CNS drug-like properties suitable for crossing the blood-brain-barrier.
Inhibition of Hypoxia Inducible Factor 2 (HIF2a)translation for the treatment of renal cancer.
Inactivation of the von Hippel-Lindau (VHL) tumor suppressor protein (pVHL) is responsible for sporadic clear cell renal cancers (RCC). pVHL targets both HIF1a and HIF2 a for ubiquitination and degradation. There is compelling evidence that inactivation of HIF2a is necessary and sufficient for the tumor suppressor function of pVHL. Professor Othon Iliopoulos at Massachusetts General Hospital discovered small molecules that activate Iron Regulatory Protein 1 (IRP1) to repress HIF2a translation. In collaboration with Othon we are synthesizing analogs with improved potency and drug-like properties for use as probes in cancer models.
A novel approach to treat Charcot Marie Tooth disease (CMT).
CMT is the most common inherited peripheral neuropathy in humans, with a prevalence of ~1 in 2,500. The disorder is characterized by slowly progressive distal muscle atrophy and weakness, impaired sensation, and diminished deep tendon reflexes, with onset in the second or third decade of life. Currently, there are no treatments for this disease. Our collaborator is Professor Pragna Patel at University of Southern California, who co-discovered the novel DNA duplication encompassing the PMP22 gene associated with CMT1A1 and the unusual finding that a point mutation in PMP22 could cause a clinically indistinguishable disease classified as CMT1E. Using a cell-based HTS for drugs, which resolve the aggregates seen when a highly deleterious mutation-bearing PMP22 is expressed, Dr. Patel identified a number of interesting hits. Currently, we are conducting hit-to-lead studies on a number of hits to identify a lead series suitable for in vivo characterization.
In this process, we take lead compounds and optimize potency to establish an SAR for the series, and we identify compounds suitable for use as probes in in vitro target identification strategies.
TDP-43 Inclusion Inhibitors.
A collaboration with Professor Ben Wolozin at Boston University. His work on Alzheimer’s disease examines the role of cholesterol in the pathophysiology of Alzheimer’s disease, and stems from his discovery in 2000 that subjects taking the cholesterol-lowering medicines, termed statins, have a lower incidence of Alzheimer’s disease. His work on ALS focuses on the response of RNA metabolism and protein translation to stress. TDP-43 is one of the primary proteins linked to the neuropathology of amyotrophic lateral sclerosis (ALS), and also accumulates as intracellular aggregates in Alzheimer’s disease (AD) and frontotemporal dementia (FTLD-TDP). Pathological TDP-43 forms insoluble protein aggregates that accumulate predominantly in the cytoplasm, but it can also appear in the nucleus. The mechanism underlying formation of TDP-43 pathology highlights novel pathways in neurodegenerative diseases, which potentially opens new avenues to pharmacotherapy of these illnesses.
We are working with a number of collaborators to generate preliminary data to establish potential new projects and drug discovery efforts. This may include:
- analysis of hits from screening;
- synthesis of screening hits, reference compounds, and small sets of compounds to establish SAR;
- assistance with grant applications; and
- patent writing and strategy.