PROTAC: Small Molecule Drugs Back to the Stage

Traditional drug research and development mainly focuses on directly regulating the activity of proteins or enzymes to treat diseases, and controls protein functions mainly through the pharmacological action mode of "occupancy-driven". The development and application of protein activity regulators are always the mainstream direction of drug R&D. However, it is estimated that only 10% of proteins can be regulated by small molecules, and 10% of proteins that can be regulated by biological macromolecules are on the cell surface, and up to 80% of the proteins cannot be controlled with existing drugs.

Unlike traditional regulators of protein activity, the Protac ubiquitinates the disease-causing protein that can be degraded by the proteasome. In theory, PROTAC only provides binding activity as an event-driven pharmacological mode of action without inhibiting the functional activity of the target protein. It is believed that the activity of PROTAC needs not to be very high. With the continuous development and improvement of PROTAC technology, it is popular among many international pharmaceutical giants.

The history of PROTAC

The origin of the Proteolysis Targeting Chimeric (PROTAC) can be traced back to the process of protein degradation regulated by Ubiquitin (Ub), which was jointly discovered by Israeli scientist Aaron Ciechanover, Avram Hershko, and American scientist Irwin Rose, who were awarded the Nobel Prize in 2004. Researchers represented by Raymond J. Deshaies, a member of The American Academy of Arts and Sciences (abbreviation: AAAS) and Craig M. Crews, the founder of Arvinas proposed the concept of PROTAC in 2001.

PROTAC is a special protein degradation technology, which uses the Ubiquitin proteasome pathway, a naturally occurring protein degradation pathway in cells, to remove specific proteins that need to be degraded. Proteins with abnormal structures or functions in cells are marked with polyubiquitination by a series of enzymes (ubiquitinase E1, E2, E3), and then transferred to the proteasome for degradation.

A PROTAC molecule includes two key domains, one that specifically binds to the target protein to be degraded, and the other that binds to E3 ligase, which are connected by a specific linker. The PROTAC molecule connects the target protein with the E3 ligase through the above two key domains, and the target protein is ubiquitinated then. Multiple ubiquitin tags are formed after multiple rounds of ubiquitination. The target protein after polyubiquitination is recognized by proteasome and degraded.

On March 26, 2019, Arvinas announced that their recombinant protein degrading agent ARV-110 officially launched a phase I clinical trial to treat patients with metastatic castration-resistant prostate cancer (mCRPC). ARV-110 is an oral PROTAC protein degrading agent for plasma androgen receptor (AR), which is the first time that a new therapy of replication protein degrading agent started human clinical trials.

On June 26, 2019, Arvinas announced that their Investigational New Drug (IND) Application for the treatment of locally advanced or metastatic ER-positive/HER2-negative breast cancer with its protein degrading agent ARV-471 targeting the estrogen receptor (ER) was approved by the US FDA, and the Phase I clinical trial was expected to start in the third quarter of 2019.

Dr. Andrew Phillips, CEO of C4 Therapeutics, revealed that the PROTAC field would usher in a period of explosion from 2019 to 2021.

The industrialization of PROTAC technology is increasingly popular in recent years. Famous biotechnology companies in this field include Captor therapeutics, Nutrix therapeutics, Cedilla therapeutics, Vividion therapeutics, Cullgen, Kymera, Creative Biolabs, etc. The major pharmaceutical companies that deploy PROTAC include Pfizer, Merck, Genentech, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Celgene, Amgen, Eli Lilly, Gilead, AbbVie, Johnson & Johnson, etc.

Judging from the current global trend, biological drugs are becoming increasingly popular, and small molecule drugs are gradually losing their weight. The investment of a large amount of venture capital and the cooperation of pharmaceutical giants will promote the rapid development of PROTAC. The era of small molecule protein degradation agent is coming.

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