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Small molecule chemical probes for the targeted degradation of dual epigenetic proteins towards novel anti-cancer therapeutics

Primary Supervisor: Dr James Hodgkinson, Department of Chemistry

Secondary supervisor: Professor Shaun Cowley

PhD project title: Small molecule chemical probes for the targeted degradation of dual epigenetic proteins towards novel anti-cancer therapeutics

University of Registration: University of Leicester

Project outline:

The mode of action of most bioactive small molecules is by inhibiting protein function, most commonly by inhibiting enzyme catalysis or acting as a receptor antagonist. In recent years the identification of small molecules not only capable of inhibiting protein function, but also degrading it by recruitment of the proteasome, has led to a paradigm shift in chemical biology (Lai & Crews, 2017, Nature drug discovery, 16, 101-114). Small molecules capable of inducing protein degradation demonstrate significant advantages over small molecule protein inhibitors, including, enhanced selectivity for the target protein and higher tolerance to drug induced resistance mechanisms, potentially leading to reduced side effects in patients while also maintaining drug efficacy.

We reported the first synthesis of small molecule chemical degraders of Histone Deacetylase (HDAC) enzymes 1, 2 and 3 (Smalley et al, 2020, Chemical Communications, 56, 4476-4479), key epigenetic regulatory proteins. These molecules degrade Class I HDAC enzymes in colon cancer cells inhibiting colon cancer cell proliferation and inducing cell death. The identification of these novel degraders as chemical tools to probe Class I HDACS, as well as their potential therapeutic benefits, is an exciting discovery (https://www.youtube.com/watch?v=kYi21aFrR2U).

In this studentship we will explore the synthesis and biological evaluation of novel small molecules that target multiple epigenetic protein targets for degradation. This strategy could be especially beneficial in the class I HDAC multi-protein CoREST complex. This tripartite complex consists of Histone Deacetylase 1/2 (HDAC1/2), Lysine Specific Demethylase 1A (LSD1) and REST corepressor 1 (CoREST). We aim to synthesise and evaluate novel small molecules capable of dual degradation of both LSD1 and HDAC1/2 present within the CoREST complex. Such dual degraders could potentially enhance selectivity for the CoREST complex, and not only inhibit enzymatic activity of HDAC1/2 and LSD1 in the complex, but via degradation of these two important components of the complex, compromise the CoREST complex as a whole. Such molecules will serve as powerful chemical tools to study the CoREST complex in cell biology and its role in disease.

Objective 1: Investigate structural modifications to established small molecule HDAC degraders to incorporate a LSD1 binding ligand.

Objective 2: Synthesize a series of dual functionalised LSD1 and HDAC small molecule degraders.

Objective 3: Asses dual functionalised molecules for binding LSD1 and HDAC1/2 in the CoREST complex in vitro.

Objective 4: Evaluate the degradation profile of LSD1 and HDAC1/2 in HCT116 cells with dual degraders and assess their effects on cancer cell viability.

BBSRC Strategic Research Priority: Integrated Understanding of Health: Ageing & Pharmaceuticals

Techniques that will be undertaken during the project:

Medicinal Chemistry/ Synthetic organic chemistry, Cell culture, Western blotting, In vitro fluorescence assays, Flow cytometry (FACS) analysis and cell viability assays.

Contact: Dr James HodgkinsonLink opens in a new window, University of Leicester