Topic: Targeting the undruggable targets in cancer and neurodegenerative diseases
Speaker: Professor Jetze Tepe - Michigan State University
Host: Professor Xuefei Huang
Date: Thursday, October 24, 2019
Time: 4:10 PM
Location: 136 CEM
Undruggable proteins are proteins that cannot be targeted pharmacologically.1 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.2 After decades of intense research, c-MYC has yet to succumb to small molecule pharmacological regulation.1 Of all human organs and tissues, the brain expresses one of the highest levels of IDPs. 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.3 Currently, there are no treatment options available to treat or slow these neurodegenerative diseases.
Over the last three years, our lab has developed a new therapeutic approach that prevents the accumulation of disease driving IDPs.4-8 This seminar will discuss our progress of this new strategy and its cellular and in vivo efficacy.
1. Dang, C. V., Reddy, E. P., Shokat, K. M. & Soucek, L. Drugging the 'undruggable' cancer targets. Nat. Rev. Cancer 17, 502-508, (2017).
2. Carroll, P. A., Freie, B. W., Mathsyaraja, H. & Eisenman, R. N. The MYC transcription factor network: balancing metabolism, proliferation and oncogenesis. Front. Med. 12, 412-425, (2018).
3. 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).
4. Njomen, E. & Tepe, J. J. Regulation of Autophagic Flux by the 20S Proteasome. Cell Chem. Biol. 26, 1283-1294 e1285, (2019).
5. Njomen, E. & Tepe, J. J. Proteasome Activation as a New Therapeutic Approach To Target Proteotoxic Disorders. J. Med. Chem. 62, 6469-6481, (2019).
6. Jones, C. L. & Tepe, J. J. Proteasome Activation to Combat Proteotoxicity. Molecules 24, (2019).
7. Njomen, E., Osmulski, P. A., Jones, C. L., Gaczynska, M. & Tepe, J. J. Small Molecule Modulation of Proteasome Assembly. Biochemistry 57, 4214-4224, (2018).
8. 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).