College of Medical, Veterinary & Life Sciences

PDE4 PROTACs

^{Industry collaboration with BioTheryX to explore the therapeutic properties of PROTAC bio-tools.}

Professor George Baillie and his research team based at the School of Cardiovascular & Metabolic Health (SCAMH) at the University of Glasgow (UofG) developed a partnership with a USA biopharmaceutical company BioTheryX Inc., San Diego, USA to explore the role of PDE4 PROTACS as therapeutics in several diseases. Funding support to enable stakeholder meetings and the establishment of the collaboration has been supported by the Translational Research Initiative (TRI) within the UofG’s College of Medical, Veterinary and Life Sciences (MVLS). Further awards by the TRI, the Medical Research Council (MRC), and Medical Research Scotland (MRS) enabled the background and developmental research to explore the therapeutic potential of the therapeutic innovations.

The main area of interest for Professor Baillie’s group have been signalling proteins involved in pathogenesis of a variety of cardiac and cancer conditions that are associated with inflammation and abnormal cell proliferation. After more than two decades of dedicated work, the group have identified and characterised a comprehensive collection of bio-tools to research phosphodiesterase-4 (PDE4) [Figure 1]. This has been recognised as a promising therapeutic target in a variety of conditions including multiple sclerosis, Alzheimer’s disease, traumatic brain injury, chronic obstructive pulmonary disease, and several types of cancer. This work generated significant impact, leading to over 150 peer-reviewed publications in esteemed journals, and a number of new research projects to explore therapeutic avenues.  The characterisation of this enzyme family sparked an interest from BioTheryX .

_{Figure 1. PROTACs against PDE4.}

BioTheryX is a US-based company with an interest in discovering and developing targeted protein degraders to address severe unmet patient needs. Their particular interest in PROteolysis TArgeting Chimeras (PROTACs) and bifunctional molecules shared a common focus with Prof Baillie’s work and discovery pipeline and sparked a mutual interest for new collaborations. PROTACs are novel molecules that link the protein of interest (POI) with an E3 ligase which results in the silencing and redirecting the POI to the proteasomal degradation machinery inside the cell. This mechanism can be employed in the treatment of inflammatory or cancerous diseases characterised by the presence of dysfunctional or overactive proteins, such as atopic dermatitis, acute myeloid leukaemia or breast cancer. Targeting specific proteins can potentially minimise side effects or overcome drug resistance which commonly occur during conventional therapies for these conditions. This class of therapeutics has multiple health and socioeconomic benefits, as they can enhance patients’ quality of life and extend their lifespan, promote better health outcomes, and provide them with more independence by reducing hospitalisation time.

PROTACs that could selectively inhibit and/or degrade PDE4 aligned well with both the discovery pipeline of BioTheryX for auto-immune and inflammatory diseases, and the work conducted by Prof Baillie and his group at UofG. Given their common interests, Prof Baillie pursued a collaboration with BioTheryX to explore new avenues towards impact, by combining the academic strengths of his group with the industrial expertise and manufacturing capacities of BioTheryX.  

The TRI facilitated the development of the framework for a partnership through a TRI MRC Proximity to Discovery grant in 2019, and a TRI MRC Confidence in Concept award in 2021. This support facilitated the early development of his innovation, and enabled Prof Baillie to travel to BioTheryX Headquarters in San Diego, USA, to meet with the BioTheryX team and lay the foundations for a successful collaboration. After a series of successful meetings, BioTheryX and UofG entered a partnership, contributing funds, knowledge, and expertise in order to tackle some of healthcare’s most pressing issues. This initiative led to over £300K of follow-on funding, including the establishment of a 2-year postdoctoral research fellowship and co-funding for a  a PhD studentship, with internal contributions provided by the college of MVLS. The work that resulted from this collaboration established the groundwork in research on disease systems where PDE4 PROTACs could be utilised and successfully advanced to lead optimisation and clinical trials initiated by BioTheryX, in auto-immune diseases such as arthritis.

The success behind this collaboration has been an outcome of the translationally focused and innovation-driven mindset of Prof Baillie and his team. Their hard work and commitment to scientific advances was recognised and supported by the TRI and college of MVLS and attracted the interest of BioTheryX, leading to a successful collaboration, expansion of scientific knowledge and expertise, and promising new therapeutic targets for the advancement of healthcare.

Moreover, through this initiative, the team established links that lay the foundations for a new collaboration between Prof. Baillie, Dr. Melissa Bowerman (a leader in Acrodysostosis research from Keele University) and Katalytic Therapeutics Inc. This collaboration resulted in a successful application for a shared £1 Million grant from the MRC. This larger collaborative work is expanding the investigation of PROTACs that are capable of downregulating PDE4D enzymes, with a view to developing novel therapeutics for Acrodysostosis Type 2.