Proteolysis targeting chimeras (PROTAC)-related drug development is becoming popular.
Just recently, Monte Rosa Therapeutics announced the completion of a $32.5 million Series A financing to develop small molecule drugs that degrade proteins associated with diseases.
The current industry star is Arvinas using PROTAC to treat castration-resistant prostate cancer drug ARV-110. This is the world's first PROTAC drug to enter clinical trials. In May 2019, ARV-110 received FDA fast-track approval and is currently in clinical phase I research. On May 23, 2020, the initial clinical Phase I data released by Arvinas showed that ARV-110 has good oral availability, safety and tolerability.
On May 19, 2020, Roche and Vividion Therapeutics announced global exclusive license agreement to use the latter's proteomics screening platform and proprietary small molecule database to develop new protein degradation therapy. In addition, GlaxoSmithKline (GSK), Merck (MSD), Pfizer, Bayer and many other global pharmaceutical companies have also reached more than a dozen collaborations with different companies on protein degradation therapies.
The capital market also favors this area. The two companies focused on this innovative therapy, Kymera and Nulix, both completed financing of more than US$100 million in March 2020. Cedilla Therapeutics, Monte Rosa Therapeutics and other companies have also received financing.

PROTAC is considered by the industry as a big helper for small molecule drug development.
The structure of PROTAC: one end is a ligand that targets the target protein, and the other end is a ligand that binds E3 ubiquitin ligase, which is then connected by a linker of a certain length. This system marks a protein that needs to be degraded by adding a small protein called "ubiquitin" to a defective or damaged protein. These ubiquitin-labeled proteins are then sent to the cell. The proteasome is broken down into short peptides and amino acids for cells to synthesize other proteins.
Most traditional small molecule drugs or monoclonal antibodies need to bind to active sites on enzymes or receptors to function. It is estimated that 80% of proteins in human cells lack this site. However, PROTAC "capture" proteins are not restricted by these sites-in 2018, the London Cancer Institute produced a small molecule that can bind to a transcription factor that has no active site. Therefore, the industry believes that protein degradation therapy can target targets that traditional small molecule inhibitors cannot target, or produce effects that small molecule inhibitors cannot.
Will it be the next hot field after PD-1?
As well known, PROTAC is traced back to the patent application filed by two researchers of Proteinix (John Kenten and Steven Roberts) in 1999, which uses a small molecule compound to degrade a specific protein based on the ubiquitin mechanism, but it is believed that this method complicates drug research and development and is ultimately not adopted.
Two years later, Dr. Craig Crews and Dr. Raymond Deshaies designed a series of bifunctional small molecules based on peptide compounds to induce the degradation of methionine peptidase 2 (MetAP-2), and formally proposed the concept of PROTAC. However, because these compounds, which are based on large and bulky peptides, are difficult to connect to cells, the first generation of PROTACs failed. Until 2008, the Crews team designed the second-generation PROTACs that can be used to degrade the androgen receptor (AR) based on E3's ubiquitin protein ligase MDM2. In 2013, Craig Crews established Arvinas, the world's first company to develop drugs using PROTAC technology.
Craig Crews is not the only researcher focusing on protein degradation therapies. This treatment also attracts the attention of James Bradner, the current head of research and development at Novartis.
In 2010, James Bradner followed a paper published by the team of Hiroshi Handa, a professor at Tokyo Medical University. In the 1950s, thalidomide was used to treat symptoms such as nausea in pregnant women, but it was later confirmed that it can cause serious birth defects in babies. Handa Hiroshi's team used thalidomide as a bait for trapping proteins in cells and found that the drug can hook and block the activity of ubiquitin ligase. This inhibition can affect limb growth and development. James Bradner realized that thalidomide could be used to design a new type of PROTAC. In 2015, James Bradner published a new generation of PROTAC molecules based on thalidomide analogues in Science.
The Crews team also designed a new generation of PROTACs based on the new E3 ubiquitin ligase VHL (Von Hippel-Lindau) and CRBN ligands, which reduced the level of various proteins by more than 90%, which became a strong proof of the drugability of PROTAC.
The huge breakthrough in scientific research made the field of PROTACs break out in 2015. Raymond Deshaies, who worked with Craig Crews before leaving the PROTAC field, predicted this year: "PROTACs may become a major new drug, which may exceed the two most popular drug development areas in history-protein kinase inhibition Agents and monoclonal antibodies!"
At present, many startups have appeared in this field. Startups including Arvinas, Kymera Therapeutics, Nulix Therapeutics, C4 Therapeutics, Vividion Therapeutics have already cooperated with Roche, Biogen, GSK, Sanofi, Gilead, Well-known pharmaceutical companies such as Bayer, Pfizer, and MSD have reached cooperation in protein degradation therapy.
1. Arvinas
Time of establishment: 2013
Main products: ARV-110 (treatment of castration-resistant prostate cancer), ARV-471 (treatment of breast cancer)
Financing: NASDAQ listing
2. Kymera Therapeutics
Time of establishment: 2016
Main product: KYM-001 (Treatment of B-cell lymphoma carrying MYD88 gene mutation)
Funding: March 12, 2020, completed a $102 million Series C financing
3.Nurix Therapeutics
Time of establishment: 2009
Main products: chimeric targeting molecules targeting BTK (treatment of B-cell malignant tumors), oral CBL-B ligase inhibitors (a new type of immune tumor drug)
Funding situation: On March 12, 2020, the $120 million financing was completed
4. C4 Therapeutics
Time of establishment: 2015
Main products: "Degronimid" small molecule
Financing: Round A financing
5. Cedilla Therapeutics
Time of establishment: 2018
Main products: Undisclosed R&D pipeline
Financing: A round of financing of USD 56.2 million was completed in 2018
6. Vividion Therapeutics
Time of establishment: 2013
Main products: Several drug candidates with high selectivity for proteins are being developed
Financing: on May 8, 2020, a $8,200 Series B financing was completed
7. Monte Rosa Therapeutics
Time of establishment: 2018
Main product: a small molecule that can regulate the activity of ubiquitin ligase
Financing situation: On May 26, 2020, A round of financing of USD 32.5 million was completed
Founded in 2004, Creative Biolabs has a professional research team dedicated to the research and development of drug discovery and engineering. Through the team's relentless exploration, the company provides the entire one-stop PROTAC-based drug development services from early discovery to pre-clinical evaluation and clinical trials.