Targeting the Undruggable Targets in Cancer and Neurodegenerative Diseases

Speaker: 
Dr. Jetze Tepe, Professor of Chemistry, Michigan State University
Location: 
RHPH 164
Date / Time: 
Thursday, March 5, 2020 - 4:00pm
Host: 
Dr. Benita Sjogren
Abstract: 

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.

References:

  1. Thibaudeau, T. A., Anderson, R. T. & Smith, D. M. A common mechanism of proteasome impairment by neurodegenerative disease-associated oligomers. Nat. Commun. 9, 1097, (2018).
  2. Njomen, E. & Tepe, J. J. Regulation of Autophagic Flux by the 20S Proteasome. Cell Chem Biol 26, 1283-1294 e1285, (2019).
  3. Njomen, E. & Tepe, J. J. Proteasome Activation as a New Therapeutic Approach To Target Proteotoxic Disorders. J. Med. Chem. 62, 6469-6481, (2019).
  4. Jones, C. L. & Tepe, J. J. Proteasome Activation to Combat Proteotoxicity. Molecules 24, 2481, (2019).
  5. Njomen, E., Osmulski, P. A., Jones, C. L., Gaczynska, M. & Tepe, J. J. Small Molecule Modulation of Proteasome Assembly. Biochemistry 57, 4214-4224, (2018).
  6. Jones, C. L., Njomen, E., Sjogren, B., Dexheimer, T. S. & Tepe, J. J. Small Molecule Enhancement of 20S Proteasome Activity Targets Intrinsically Disordered Proteins. ACS Chem. Biol. 12, 2240-2247, (2017).

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