I Technical Principle of PROTAC
Five elements is developing a new class of drugs that engage the body’s own natural protein disposal system to treat cancers and other difficult-to-treat diseases. As a potential improvement over traditional small molecule inhibitors, PROTAC™ (Proteolysis-Targeting Chimera) protein degraders are able to degrade disease-causing proteins through the cell’s Ubiquitin/Proteasome System, which routinely degrades proteins. PROTAC™ protein degraders work by recruiting an E3 ligase to tag the target protein for ubiquitination and degradation through the proteasome, a large complex that degrades the ubiquitinated protein into small peptides. After the protein is degraded, the drug is released to continue its degradation mission.
II The Advantages of PROTAC
When the first human genome was sequenced, researchers finally got a glimpse of the true dimensions of our proteome—the tens of thousands of proteins responsible for sickness and health. Ever since, scientists have explored the morass for drivers of diseases, generating a long wish list of proteins they’d like to control.
But even as they add to the list, drug hunters live with a maddening reality: So many of its entries are out of reach. Conventional small-molecule and antibody drugs can access only about 20% of the proteins we make. So when a new technology comes along promising to tap into the other roughly 80%, everyone pays attention. And PROTAC is the attention.
INHIBITION VS. DEGRADATION
By removing target proteins directly rather than merely blocking them, our PROTAC™ protein degraders may provide multiple advantages over small molecule inhibitors.
1. Cellular Potency and Catalytic Effect
Most small molecule-induced pharmacology is driven by the requirement for maintenance of high equilibrium target occupancy which in turn often requires high drug dose. Such high dose agents have historically been associated with a higher likelihood of exhibiting (often off-target) toxic effects and eventual drug resistance.
Protacs, acting as agonists to catalytically initiate a degradation cascade,
are no longer limited by this paradigm. Instead, a low level of target protein occupancy may be sufficient to maintain a rate of protein degradation that quickly depletes a high proportion of cellular protein giving the desired pharmacological effect.
2. Potential for Extended Pharmacodynamic Duration of Action.
A Protac that can rapidly deplete the entire pool of a slowly resynthesized protein could deliver significant pharmacology from short-term drug exposure with a subsequent duration of effect of the order of hours/days delivering sustained efficacy despite the drug being present at low or even undetectable levels for a significant proportion of the dosing interval.
3. The Opportunity to Mediate Novel Pharmacology.
Many drug targets present particular challenges to drug discovery. They may not have a specific catalytic active site whose function can be blocked. in contrast to functional inhibitors , a Protac-induced degradation only needs to facilitate E3 ligase recruitment and initiation of the degradation cascade. As the ligand itself need not possess a specific function, it can bind anywhere on the target protein (or indeed on another protein in complex with the target), greatly increasing the probability of finding a suitable ligand when using appropriate binding site agnostic (biophysical) screening approaches.
 Targeted protein degraders are redefining how small molecules look and act. C&EN News. 2018, 96 (8).
 Protac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones? J. Med. Chem. 2018, 61, 444−452.
III Unique advantages
Five Elements has a scientific team experienced in small molecule drugs development. Based on our previous researches and work to build a PROTAC platform with independent intellectual property rights.
Five Elements has advantages in PROTAC technology by LINKER optimization and develops PROTAC drugs to target EGFR in non-small cell lung cancer, applying PROTAC technology to the development of new drugs which solve the current drug resistance problem, enhance drug efficacy and patient survival rate, and provide new perspectives for the development of PROTAC drugs in other cancer types.