Novel E3 ligase inhibitors for treatment of neurodegenerative disease

DESCRIPTION provided by applicant Progressive loss of cognitive skills a hallmark of neurodegenerative diseases such as Alzheimerandapos s AD represents a major challenge to healthcare implementation No satisfactory treatments for AD currently exist and multiple approaches will be necessary for successful therapeutic management Among these approaches is effective pharmacologic intervention to ameliorate cognitive deficits associated with AD and other neurodegenerative diseases Ubiquitin E ligases are a class of molecular target recently linked to a variety of pathologies including synaptic function and regulation of te response to oxidative stress in neurons and other cell types IDOL is one such ligase it is known to ubiquitylate and promote the degradation of certain receptors including ApoER and VLDLR which are the major receptors for the glycoprotein Reelin in the brain Reelin is a principal regulator of memory cognition via signal transduction mediated by ApoER and VLDLR Reelin binding increases long term potentiation and synaptic plasticity Numerous knock out and knock in studies as well as murine models show that Reelin exerts a positive effect on learning and memory thus augmentation of Reelin signaling is very likely to offer benefit in treating cognitive decline in AD and related diseases Because IDOL is responsible for down regulating Reelin the therapeutic hypothesis addressed in the proposed project is that IDOL is a tractable novel target for developing small molecule inhibitors that will augment Reelin signaling Inhibitors of IDOL are expected to increase ApoER and VLDLR levels in the brain and enhance Reelin mediated synaptic plasticity Using a thermal shift based pilot screen Progenra has discovered several IDOL inhibitors and preliminary data demonstrate that one of these IDOL inhibitors P stabilizes ApoER In the proposed project novel small molecules that enhance or stimulate Reelin signaling in the brain by interfering with IDOL and stabilizing ApoER and VLDLR will be discovered and advanced toward pre clinical development Inhibitors already in hand will be developed by chemical optimization and additional inhibitors will be identified by further screening of Progenraandapos s entire small molecule library and optimized similarly Selected inhibitors will be evaluated using a combination of biochemical cellular and in vivo model systems for their ability to stabilize ApoER and VLDLR as well as to modulate Reelin signaling biomarkers In Phase II the most promising compounds will advance into preclinical development using appropriate animal models for memory and cognition PUBLIC HEALTH RELEVANCE The proposed project addresses the progressive loss of cognitive skills observed in neurodegenerative diseases such as Alzheimerandapos s Disease AD Preventing or reversing this decline will be an important component of future treatment strategies for AD Progenra has discovered inhibitors of a ubiquitin pathway enzyme IDOL that are able to stabilize two neuronal receptor molecules ApoER and VLDLR that are important in promoting cognition and memory It is proposed to develop these molecules and others like them for treatment of AD and related neurodegenerative diseases