Chemical Tools for Probing Histone Deacetylase Multiprotein Complexes in Disease
Lead Research Organisation:
University of Leicester
Department Name: Chemistry
Abstract
The development of new chemical tools and probes is vital to understanding the functions of multifaceted proteins and enzymes in the cell and their role in disease. Many enzymes catalyse chemical modifications to DNA and DNA associated proteins regulating which genes are 'switched on' and 'off', often termed the epigenome. Histone deacetylases (HDAC) are a class of enzyme that remove acetyl groups from DNA associated histone proteins. The presence of many HDAC isoenzymes in the cell, with structural similarity, makes probing these enzymes selectively a challenge. Further to this, the same HDAC isoenzyme can be incorporated as a catalytic sub-unit into a number of much larger multiprotein corepressor complexes, whereby the complex is essential to the distinct biological function of the HDAC. Abnormal HDAC activity is associated with diseases including cancer and Alzheimer's yet current drugs lack HDAC enzyme selectivity and are associated with debilitating side effects.
The proposed research will deliver novel chemical tools designed to modulate HDAC enzymes with multiprotein complex selectivity. Designing compounds to selectively target a specific HDAC complex is a novel approach towards probing the function of such complexes with significant therapeutic potential. This will be achieved by three objectives. Objective one involves the preparation of dual functionalised warhead peptides designed to bind two enzymatic sites simultaneously in a specific complex. Objective two focuses on the development of compounds to facilitate selective degradation of a sub-unit enzyme required for multiprotein complex structural integrity and function. Objective three broadens on the approaches from objective two investigating the synthesis and validation of other compounds to degrade other histone deacetylase enzymes with complex selectivity. The chemical tools developed will have important applications in studying the roles of HDAC multiprotein complexes in disease, and the tools will also be used for future medicinal compound development to treat diseases such as cancer.
The proposed research will deliver novel chemical tools designed to modulate HDAC enzymes with multiprotein complex selectivity. Designing compounds to selectively target a specific HDAC complex is a novel approach towards probing the function of such complexes with significant therapeutic potential. This will be achieved by three objectives. Objective one involves the preparation of dual functionalised warhead peptides designed to bind two enzymatic sites simultaneously in a specific complex. Objective two focuses on the development of compounds to facilitate selective degradation of a sub-unit enzyme required for multiprotein complex structural integrity and function. Objective three broadens on the approaches from objective two investigating the synthesis and validation of other compounds to degrade other histone deacetylase enzymes with complex selectivity. The chemical tools developed will have important applications in studying the roles of HDAC multiprotein complexes in disease, and the tools will also be used for future medicinal compound development to treat diseases such as cancer.
Planned Impact
Therapeutic agents have been approved by the FDA targeting epigenetic proteins and numerous compounds are currently in clinical trials. The epigenetics market is predicted to be valued at 16.31 billion USD by the year 2022. Considering the application of our tool compounds they will be of significant interest for potential translational funding opportunities, and collaborative opportunities, with the pharmaceutical industry and medical research charities in the UK looking for novel approaches towards drugging targets. This will contribute to the UK's economy in the drug discovery and life sciences sectors. Through a number of LISCB enterprise events such companies and charities will be informed and engaged with the research over, and beyond, the two year period of the proposed project.
Histone deacetylase enzymes and their complexes have been linked to diseases that plague modern day society. These include; cancer, cardiovascular diseases, neurodegenerative diseases such as Alzheimer's and even drug addiction. Cancer and heart disease are one of the top causes of mortality in in the UK. While an aging population has resulted in increasing incidences of neurodegenerative diseases such as Alzheimer's and dementia placing a real burden on carers in society and the NHS. It is envisaged that this research programme will lead to future drugs that will contribute to alleviating the socioeconomic burden caused by these diseases. This will contribute to a significant improvement in UK citizen's quality of life, health and reduced mortality rates. Throughout the project conference presentations, posters, publications and other outputs will be publicised to other scientists and the public by a Hodgkinson research group twitter feed, department of chemistry twitter feed, University of Leicester Yammer site, and the Hodgkinson department of chemistry and LISCB websites. The research will also be highlighted in university open days to prospective students and during university STEM school visits.
The PDRA will gain essential skills and training in multiple aspects of chemical biology. The research will be carried out in the interdisciplinary environment of LISCB. The PDRA will have daily project meetings with the PI and will attend regular joint group meetings between the Hodgkinson, Schwabe and Cowley groups to present their findings. Within the first year of the project the PDRA will have performed and gained skills in; automated peptide synthesis, fluorescence based assays, and hands on experience using cryo-electron microscopy. In the final year the PDRA will advance their synthetic skills and be competent in cell culture experiments and western blotting. This broad skillset will prepare the PDRA for a future career in chemical biology in academia or industry. The PDRA will also have the opportunity to supervise undergraduate and postgraduate students in the Hodgkinson research group gaining management skills. The PDRA will have the opportunity to present at national conferences, including RSC chemical biology meetings, and one international conference. Overall this training will contribute to and strengthen the chemical biology community in the UK.
Histone deacetylase enzymes and their complexes have been linked to diseases that plague modern day society. These include; cancer, cardiovascular diseases, neurodegenerative diseases such as Alzheimer's and even drug addiction. Cancer and heart disease are one of the top causes of mortality in in the UK. While an aging population has resulted in increasing incidences of neurodegenerative diseases such as Alzheimer's and dementia placing a real burden on carers in society and the NHS. It is envisaged that this research programme will lead to future drugs that will contribute to alleviating the socioeconomic burden caused by these diseases. This will contribute to a significant improvement in UK citizen's quality of life, health and reduced mortality rates. Throughout the project conference presentations, posters, publications and other outputs will be publicised to other scientists and the public by a Hodgkinson research group twitter feed, department of chemistry twitter feed, University of Leicester Yammer site, and the Hodgkinson department of chemistry and LISCB websites. The research will also be highlighted in university open days to prospective students and during university STEM school visits.
The PDRA will gain essential skills and training in multiple aspects of chemical biology. The research will be carried out in the interdisciplinary environment of LISCB. The PDRA will have daily project meetings with the PI and will attend regular joint group meetings between the Hodgkinson, Schwabe and Cowley groups to present their findings. Within the first year of the project the PDRA will have performed and gained skills in; automated peptide synthesis, fluorescence based assays, and hands on experience using cryo-electron microscopy. In the final year the PDRA will advance their synthetic skills and be competent in cell culture experiments and western blotting. This broad skillset will prepare the PDRA for a future career in chemical biology in academia or industry. The PDRA will also have the opportunity to supervise undergraduate and postgraduate students in the Hodgkinson research group gaining management skills. The PDRA will have the opportunity to present at national conferences, including RSC chemical biology meetings, and one international conference. Overall this training will contribute to and strengthen the chemical biology community in the UK.
Publications
Baker IM
(2023)
Comprehensive Transcriptomic Analysis of Novel Class I HDAC Proteolysis Targeting Chimeras (PROTACs).
in Biochemistry
Cross JM
(2022)
A 'click' chemistry approach to novel entinostat (MS-275) based class I histone deacetylase proteolysis targeting chimeras.
in RSC medicinal chemistry
Patel U
(2023)
PROTAC chemical probes for histone deacetylase enzymes.
in RSC chemical biology
Smalley JP
(2024)
MDM2 Antagonist Idasanutlin Reduces HDAC1/2 Abundance and Corepressor Partners but Not HDAC3.
in ACS medicinal chemistry letters
Smalley JP
(2020)
PROTAC-mediated degradation of class I histone deacetylase enzymes in corepressor complexes.
in Chemical communications (Cambridge, England)
Smalley JP
(2022)
Optimization of Class I Histone Deacetylase PROTACs Reveals that HDAC1/2 Degradation is Critical to Induce Apoptosis and Cell Arrest in Cancer Cells.
in Journal of medicinal chemistry
Smalley JP
(2020)
Bifunctional HDAC Therapeutics: One Drug to Rule Them All?
in Molecules (Basel, Switzerland)
Williams GM
(2020)
HDAC3 deacetylates the DNA mismatch repair factor MutSß to stimulate triplet repeat expansions.
in Proceedings of the National Academy of Sciences of the United States of America
Description | We have discovered for the first time that enzymes and proteins involved in the regulation of gene expression, class I HDACs enzymes, also associated with diseases such as cancer, can be degraded and removed from the cell with small molecules. These small molecules can be used as 'molecular tools' to study class I HDACs in the cell and have potential for medicinal chemistry development and drug discovery. We have discovered that different small molecules can exhibit differing selectivity profiles for the differing HDAC enzymes, and that targeting HDAC1 and HDAC2 enzymes specifically may be more important for the development of anticancer drugs. We have also discovered a selective degrader of HDAC3 which may be important in other cancer cell lines yet to be tested. |
Exploitation Route | It has generated interest from industry in using the compounds from this research as tool reagents/compounds to study class I HDAC enzymes. Compounds developed from the research, due to their anticancer properties, have formed the basis of a PCT patent application and patents are currently being filed in different countries. An industrial life science company is currently in negotiations with the University of Leicester to license the compounds commercially. The findings and outcomes form the research, in the bigger picture, could lead to others developing new drugs for cancer and we are currently pursuing further funding opportunities to develop and progress these compounds further as improved tool compounds and potential medicinal compounds .Others in academia have also started exploring this novel approach since we first published in the area of PROTAC mediated class I HDAC degradation. |
Sectors | Chemicals Healthcare Pharmaceuticals and Medical Biotechnology |
Description | The research has highlighted that Class I HDAC enzymes can be targeted for degradation by small molecules. This had never been demonstrated before, and offers a new strategy for targeting Class I HDACs to treat diseases such as cancer. Academically we and others are starting to pursue this strategy, and we have filed a PCT patent application due to the new molecules anticancer properties. The molecules are now being filed for patents at national levels and a company is under negotiations with the University of Leicester to commercialise these molecules. |
First Year Of Impact | 2020 |
Sector | Chemicals,Pharmaceuticals and Medical Biotechnology |
Title | Class I HDAC degrader molecules |
Description | We have synthesised novel chemical reagents, class I HDAC PROTACs, these molecules are capable of degrading Class I HDACs in cells and can be used as research tools to study the effects of removing Class I HDAC enzymes in the cell. |
Type Of Material | Technology assay or reagent |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | We have filed a UK and PCT patent on these molecules, yet to be published. We have also had interest from others in academia and commercialisation as biochemical research tools. |
URL | https://pubs.rsc.org/en/content/articlelanding/2020/cc/d0cc01485k#!divAbstract |
Title | HDAC1/2 degrader compound JPS016 |
Description | This compound JPS016 degrades HDAC1/2 and induces apoptosis in HCT116 cancer cells. It can be used as reagent or tool compound by cell biologists and others to study HDAC1/2. |
Type Of Material | Technology assay or reagent |
Year Produced | 2022 |
Provided To Others? | Yes |
Impact | The compound JPS016 is encompassed in the PCT application 2021148811 (A1). The University of Leicester is currently filing patents at a national level on this compound including in Europe, USA, Japan and Australia. It is also in negotiations with the UK based life sciences research company to license the compound and others to sell it commercially. |
URL | https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c02179 |
Title | HDAC3 selective degrader compound JPS036 |
Description | This compound JPS036 can be used to selectively degrade HDAC3 an important epigenetic enzyme and implicated in certain cancers. Cell biologists and medicinal chemists can use these compound as a reagent to study HDAC3. |
Type Of Material | Technology assay or reagent |
Year Produced | 2022 |
Provided To Others? | Yes |
Impact | The compound JPS036 is encompassed in the PCT application 2021148811 (A1). The University of Leicester is currently filing patents at a national level on this compound including in Europe, USA, Japan and Australia. It is also in negotiations with the UK based life sciences research company to license the compound and others to sell it commercially. |
URL | https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c02179 |
Title | GSE197985 |
Description | RNA-seq differential gene expression data upon treatment of HCT116 cells with PROTACs targeting class I HDACs |
Type Of Material | Database/Collection of data |
Year Produced | 2022 |
Provided To Others? | Yes |
Impact | Allows our group and other researchers to determine the effects of gene expression on treatment of class I HDAC inhitors and PROTACs - Important for research into mode of action of potential HDAC targeting drugs. |
URL | https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE197985 |
Description | Collaboration with Dr Jean Leandro dos Santos |
Organisation | Sao Paulo State University |
Country | Brazil |
Sector | Academic/University |
PI Contribution | Professor Jean L. dos Santos research group is interested in using HDAC inhibitors to treat sickle cell anaemia. We are collaborating and he is using our expertise to help develop HDAC degrader compounds. |
Collaborator Contribution | We have received a visiting PhD student from Professor dos Santos research group to make the HDAC degrader compounds in our lab for one year. The compounds made during the studentship will be tested in sickle cell anaemia cells. The visiting studentship is funded by The São Paulo Research Foundation, FAPESP. |
Impact | Visiting PhD studentship from Sao Paulo State University for one year funded by The São Paulo Research Foundation, FAPESP. |
Start Year | 2022 |
Title | HDAC DEGRADER |
Description | The disclosure provides compounds of formula (I). The compounds may be used to degrade the Histone Deacetylase (HDAC) family of enzymes, particularly HDAC1, 2 and 3 that exist in corepressor complexes. Accordingly, the compounds may be used to treat cancer. The invention extends to pharmaceutical compositions comprising these compounds, and the use of these compounds in therapy. |
IP Reference | WO2021148811 |
Protection | Patent application published |
Year Protection Granted | 2021 |
Licensed | No |
Impact | Currently pursuing potential industrial investors. |
Description | YouTube video |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | The was a short video designed to engage potential industry and charitable partners in my research on small-molecule chemical degraders of HDACs. The video has been viewed over 900 times and has so far gained interest from prospective and current students and colleagues. |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.youtube.com/watch?v=kYi21aFrR2U |