Targeting the Undruggable Targets in Cancer and Neurodegenerative Diseases
Undruggable proteins are proteins that cannot be targeted pharmacologically. Undruggable proteins are deemed undruggable because they lack defined binding pockets and are therefore not suitable for traditional “small molecule-binding pocket” drug discovery approaches. These unstructured proteins are called intrinsically disordered proteins (IDPs). There are several notorious IDPs that have challenged researchers for decades but have still evaded pharmacological regulation. One of the most desirable, but elusive, targets in cancer therapy is the IDP oncoprotein, c-MYC. c-MYC is dysregulated in over 50% of all cancer types and drives oncogenic transformation, tumor growth and resistance. After decades of intense research, c-MYC has yet to succumb to small molecule pharmacological regulation. Disease driving dysregulated IDPs in the brain include Ab, a-synuclein and dipeptide repeats (DPRs) which are directly linked to Alzheimer’s disease, Parkinson’s disease and ALS, respectively.1Currently, there are no treatment options available to treat or slow these neurodegenerative diseases.
Over the last few years, our lab has developed a new therapeutic approach that prevents the accumulation of disease driving IDPs by small molecule activation of the 20S subcomplex of the human proteasome.2-6This seminar will discuss our progress of this new strategy and its cellular and in vivo efficacy.
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