The Development of a Piperlongumine PROTAC for Targeted TRPV2 Degradation
Lead Research Organisation:
University of Cambridge
Department Name: Chemistry
Abstract
The extent of overexpression of the calcium channel, transient receptor potential vanilloid 2 (TRPV2) has been found to positively correlate with the degree of severity of the tumour grade in glioblastoma multiforme (GBM). GBM is a very aggressive brain cancer where therapeutic options have remained intransient for more than 30 years. Previous work in the Bernardes Group has identified, through the use of machine learning and cryo-electron microscopy, that the natural product, piperlongumine (PL), is a selective allosteric antagonist of TRPV2. In an orthotopic mouse model of GBM, treatment of induced tumours with PL, formulated into a hydrogel for improved drug delivery, led to near complete tumour remission.
The project aim is to degrade, rather than inhibit, TRPV2 through the development of a PL proteolysis-targeting chimera (PROTAC). Degradation of TRPV2 with a PL PROTAC would be a valuable research tool in order to decipher the (understudied) role of TRPV2 in both physiological and pathological processes since TRPV2 remains the least characterised and understood member of the TRPV subfamily of TRP channels, despite its numerous pathophysiological roles/functions. A PL PROTAC could also provide more longer-lasting therapeutic benefits than solely a TRPV2 antagonist for an aggressive disease with great unmet need. Lastly, it could potentially be used for other diseases where aberrant TRPV2 expression is intimately implicated in the observed disease phenotype.
Analogues of PL are required to explore its structure-activity relationship (SAR) for reversible TRPV2 binding, increase its selectivity and functionalise it for PROTAC development. To this end, PL and a selection of analogues were synthesised, and synthetic approaches developed for other analogues. An intracellular calcium imaging method was tested, in collaboration with the Klenerman Lab. Lastly, the compatibility of a PL analogue with a novel hydrogel for improved drug delivery was demonstrated, in collaboration with the Scherman Group.
The project aim is to degrade, rather than inhibit, TRPV2 through the development of a PL proteolysis-targeting chimera (PROTAC). Degradation of TRPV2 with a PL PROTAC would be a valuable research tool in order to decipher the (understudied) role of TRPV2 in both physiological and pathological processes since TRPV2 remains the least characterised and understood member of the TRPV subfamily of TRP channels, despite its numerous pathophysiological roles/functions. A PL PROTAC could also provide more longer-lasting therapeutic benefits than solely a TRPV2 antagonist for an aggressive disease with great unmet need. Lastly, it could potentially be used for other diseases where aberrant TRPV2 expression is intimately implicated in the observed disease phenotype.
Analogues of PL are required to explore its structure-activity relationship (SAR) for reversible TRPV2 binding, increase its selectivity and functionalise it for PROTAC development. To this end, PL and a selection of analogues were synthesised, and synthetic approaches developed for other analogues. An intracellular calcium imaging method was tested, in collaboration with the Klenerman Lab. Lastly, the compatibility of a PL analogue with a novel hydrogel for improved drug delivery was demonstrated, in collaboration with the Scherman Group.
Organisations
Publications
Mikutis S
(2020)
meCLICK-Seq, a Substrate-Hijacking and RNA Degradation Strategy for the Study of RNA Methylation.
in ACS central science
Kiely-Collins H
(2021)
The Role of Reversible and Irreversible Covalent Chemistry in Targeted Protein Degradation
in Cell Chemical Biology
Kiely-Collins H
(2023)
Harnessing the Natural Product Piperlongumine for Targeted Protein Degradation
Description | Hosted a panel discussion about being a scientist with the Cambridge University Girls in STEM initiative at the STEMtastic LIVE! event hosted by West Suffolk College |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | The STEMtastic LIVE! virtual event involved interactive exhibits from local companies and industries, engaging workshops and high-impact shows, with a particular focus on highlighting the 'hidden STEM' in our everyday lives. I hosted a panel (3 times during the day) where postgraduate women at Cambridge in STEM fields discussed their research. There were panel discussions with audience engagement about our projects and being a scientist. 30 school children attended and asked questions about our research and being a scientist. |
Year(s) Of Engagement Activity | 2020 |
URL | https://atadastral.co.uk/news/101/ |
Description | Presentation at Girlguiding Cambridgeshire East STEM day with Cambridge University Girls in STEM initiative |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | I gave a presentation about my research project and being a scientist to 50 11-14 year old school girls at the Girlguiding Cambridgeshire East STEM day with Cambridge University Girls in STEM initiative. They were very engaged, asked lots of questions and said they wanted to become scientists! |
Year(s) Of Engagement Activity | 2020 |
URL | https://mailchi.mp/c788830a0a21/gis-test-newlsetter-6343595?fbclid=IwAR0BwBgAK-OxSDMvRjNgPOYHsjw7ScT... |