Collaborative Drug Discovery Projects
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:
Lead Optimization Projects:
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.
Restoration of Glutamate transporter protein (EAAT2) for the treatment of Alzheimer’s Disease. 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 our lead compounds in several animal models of disease, including the SOD1(G93A) mouse model of ALS and the rTg4510 mouse model of AD. Significantly, the results show that this compound has profound protective effects in these proof-of-concept disease models. Evaluation of our pre-clinical candidate in IND enabling studies is now in progress.
Relevant publications:
- Lin C-LG, Kong Q, Cuny GD, Glicksman MA. Glutamate transporter EAAT2: a new target for the treatment of neurodegenerative diseases. Future Medicinal Chemistry. 2012, 4, 1689-1700.
- Takahashi K, Kong Q, Lin Y, Stouffer N, Schulte DA, Lai L, Liu Q, Chang l, Dominguez S, Xing X, Cuny GD, Hodgetts K, Glicksman MA, Lin CG. Restored Glial Glutamate Transporter EAAT2 Function as a Potential Therapeutic Approach for Alzheimer’s Disease. Journal of Experimental Medicine 2015, 212, 319-332.
- Hodgetts K, Lin CG. Pyridazine derivatives as EAAT2 activators, WO 2017123991 A1
- Foster JB, Zhao F, Wang X, Xu Z, Lin K, Askwith CC, Hodgetts KJ, Lin CG. Pyridazine-derivatives enhance structural and functional plasticity of tripartite synapse via activation of local translation in astrocytic processes. Neuroscience 2018, 388, 224-238.
Progressive Multiple Sclerosis (PMS) is characterized by the continued and irreversible accumulation of neurologic disability. Several therapies are available to treat Relapsing Remitting MS (RRMS), but no therapy is available for PMS. This lack of disease modifying therapies reflects a conceptual deficit in our understanding of the underlying pathology in PMS. Recent findings in the lab of Professor Fran Quintana lab at Brigham and Women’s Hospital suggest that innate immune cells in the CNS (astrocytes, microglia and CNS-infiltrating macrophages) play a predominant role in disease progression during PMS. However, candidate drugs for modulating the activity of astrocytes and other CNS innate immune cells in PMS are not available. In collaboration with Fran we are synthesizing and screening novel molecules for use as probes and lead compounds for the treatment of Multiple Sclerosis.
Relevant publications:
- Rothhammer V, Quintana FJ. Role of astrocytes and microglia in central nervous system inflammation. Introduction. Semin Immunopathol. 2015, 37(6), 575-6.
- Rothhammer V, Quintana FJ. Control of autoimmune CNS inflammation by astrocytes. Semin Immunopathol. 2015, 37(6), 625-38
Towards a treatment for Spinal Muscular Atrophy (SMA). 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. There is no cure or effective treatment for SMA, and drugs that improve motor function and life expectancy are desperately needed. 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. We have discovered two distinct series of small molecules that increase SMN protein expression by two to three-fold and 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 mouse models of SMA. We recently discovered a new lead series that has good drug-like properties, including good oral pharmacokinetics and brain exposure. Evaluation of our pre-clinical candidate for the treatment of SMA in the delta-7 mouse model of SMA is currently in progress.
Relevant publications:
- Rietz A., Li H., Quist K.M., Cherry J.J., Lorson C.L., Burnett B.G., Kern N.L., Calder A.N., Fritsche M., Lusic H., Boaler P.J., Choi S., Xing X., Glicksman M.A., Cuny G.D., Androphy E.J., Hodgetts K.J. Discovery of a Small Molecule Probe That Post-Translationally Stabilizes the Survival Motor Neuron Protein for the Treatment of Spinal Muscular Atrophy. Journal of Medicinal Chemistry 2017, 60, 4594-4610.
- Choi S., Calder A.N., Miller, E.H., Anderson K.P., Fiejtek D.K., Rietz A., Li H., Cherry J.J., Quist K.M., Xing X., Glicksman M.A., Cuny G.D., Lorson C.L., Androphy E.A., Hodgetts K.J. Optimization of a series of heterocycles as survival motor neuron gene transcription enhancers. Bioorganic & Medicinal Chemistry Letters 2017, 27, 5144-5148.
- Cherry J., Calder A., Hodgetts K., Androphy E.: “SMN-upregulating small molecules” in Spinal Muscular Atrophy: Disease Mechanisms and Therapy, Eds. Sumner, Paushkin, and Ko; Academic Press, 2016, Chapter 17, 283-297. ISBN: 9780128036853.
- Calder A., Androphy E., Hodgetts K.J. Small Molecules in Development for the Treatment of Spinal Muscular Atrophy. Journal of Medicinal Chemistry 2016, 59, 10067–10083.
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. The research has led to the formation of a start-up company, Klogene Therapeutics http://www.klogene.com/.
Relevant publications:
- Abraham C.R., Mullen P.C., Tucker-Zhou T., Chen C.D., Zeldich E. Klotho Is a Neuroprotective and Cognition-Enhancing Protein. In Gerald Litwack, editor: Klotho, Vol 101, VH, UK: Academic Press, 2016, pp. 215-238.
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. In collaboration with Professor Othon Iliopoulos at Massachusetts General Hospital, we have discovered small molecules that activate Iron Regulatory Protein 1 (IRP1) to repress HIF2a translation. We are synthesizing analogs with improved potency and drug-like properties for use as probes in cancer models.
Relevant publications:
- Metelo A.M., Noonan H., Iliopoulos O. HIF2a inhibitors for the treatment of VHL disease. Oncotarget. 2015 Sep 15; 6(27):23036-7.
A novel library for CNS lead discovery. Given the inherent difficulty in discovering effective drugs for neurodegenerative diseases, and given the innovative screening approaches currently being undertaken, we believe that better CNS screening libraries will significantly improve target validation and drug discovery in academia. Combining CNS drug-like properties and an analysis of ~240 CNS drugs, we identified features that we believe can be built upon to expand novel CNS chemical and biological space. The library will be shared with academic researchers, and compounds identified from screening of the library will be useful as tools to understand disease mechanism and as leads to develop new drugs and treatments for CNS diseases.
Relevant publications:
- Hodgetts K. “CNS Drug Optimization – Medicinal Chemistry” Chapter 19 in Blood-Brain-Barrier in Drug Discovery: Optimizing Brain Exposure of CNS Drugs and Minimizing Brain Side Effects, Eds. Kerns and Li. Wiley 2015, 425.
Chemical Probes for Target Identification:
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.
Emerging Projects:
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.