PROTAC’s: Making the “undruggable,” druggable? -Rana Dawood
Stress Fibers and Microtubules in Human Breast Cancer Cells, Unsplash
Let’s delve into the latest therapy taking the scientific world by storm- PROTAC’s. So, what are PROTAC’s and why are they the focus of so many scientific minds? PROTAC stands for PROteolysis TArgeting Chimera, you can think of proteolysis as the body’s own personal protein recycling bin system, and a PROTAC as a hijacker of this system. Proteolysis is the natural breakdown of proteins in the body by these nifty little units called enzymes. A large enzyme family called E3 Ubiquitin ligase enzymes are a common PROTAC target, as they are the main protein degraders in the body. The structure of a PROTAC can be broken into three segments. The 1st binds to the target protein we want to breakdown, the 2nd segment being what binds to the E3 Ubiquitin Ligase enzyme, and the 3rd being the linker between the two to bring them together and- BAM no more protein! Sounds easy enough? Now bring that process and factor in all the complex and intertwining systems of the human body, you can imagine how complicated it can get. In reality, the triangle schematic representation below is the bare-bones visualisation of this therapeutic, imagine a long mass of
hexagons in a chemical diagram and you’re more on track.
Before we go any further into the future, let’s take a step back to the root of their genesis. All the way back to the known “father” of PROTAC’s, Professor Craig Crews. In 2001, the Crews and Deshaies groups initially proposed the idea of PROTAC technology, a novel and unique pharmacological approach that sparked conversations of interest and doubts across the scientific community. Doubts that certainly dissipated in the coming years as further research ensued, catching the attention of small biotech and large pharmaceutical companies alike. Questions that come to mind may be, why are they important? What would they be used for? PROTAC’s opened the door to pursuing previously thought “undruggable” target proteins in drug discovery, that our traditional therapies couldn’t touch. Currently under investigation is their use in the treatment of various cancers, neurodegenerative diseases, immune system diseases, viral infections, etc. In 2019 arrived the first PROTAC clinical trials, promptly leading to the 2020 discovery of two highly promising cancer targets, the oestrogen and androgen receptors. Targets that are (respectively) prevalent in breast and prostate cancer. Both found in the top 5 most common cancers globally; highlighting the impact of targeting proteins that are vital to cancer survival and progression. As with any therapeutic development, the design is not as clear cut as it may seem. One of the main challenges in PROTAC design is pharmacokinetics (how drugs enter, move around, and are excreted in the body), and side-effect minimisation. Yet, great strides are being made in this research and there are various early clinical and preclinical trials running, giving us hope. PROTAC’s have had a long and arduous journey, humbly blossoming from labs within academia, to currently dominating numerous industrial clinical trials. Our synergistic research efforts have exponentially built up over the past 2 decades, and we have no doubt that soon they will be making headlines with approved candidates. It’s exciting to see where this research will take us next and all its possible future applications, it could be said that in 2001 they revolutionised the field and paved the way for a new era of therapeutics. With neoteric terms like BacPROTAC’s and Poly-PROTAC’s popping up. Maybe even a Nobel prize could be within reach for Crews, undeniably something for us to keep an eye out for…