The Laboratory for Drug Discovery in Neurodegeneration
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.
Dr. Kevin Hodgetts
Director of Medicinal Chemistry
The Laboratory for Drug Discovery in Neurodegeneration
65 Landsdowne Street
Cambridge, Massachusetts 02139
U.S.A.
Telephone: 617-768-8640
Email: khodgetts@bwh.harvard.edu
Contact
Dr. Quintana's major research interests are the study of molecular pathways that control adaptive and innate immunity, particularly in the context of autoimmune diseases. . In collaboration with Fran we are synthesizing and screening novel molecules for use as probes and lead compounds for the treatment of Multiple Sclerosis.
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.
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.
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.
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). 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.
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.