PROTAC In Focus—Hotspot Targets Under Research

Posted by Jerry Carter on April 1st, 2021

PROTAC is a novel type of drug that is different from antibodies and traditional small molecule inhibitors, consisting of a linker and two warheads. One end of the PROTAC molecule binds to the target protein, and the other binds to the E3 ubiquitin ligase that can mark the target protein as defective or damaged by attaching a small protein called ubiquitin to it. After that, the cell's proteasome recognizes and degrades the labeled target protein. The drugs developed based on PROTAC technology are also called protein degradants.

The discovery of PROTAC traced back to 2001 when Dr. Raymond Deshaies of California Institute of Technology and Professor Craig Crews of Yale University described a peptide-based PROTAC in a PNAS paper. However, that PROTAC, which is based on bulky peptides acting as a link, is less active in human cells. Since then, Professor Crews and colleagues have been exploring for improvements. In 2008, there was pivotal progress that the first small molecule PROTAC was developed. The team designed a small molecule degrading agent based on the E3 ligase MDM2 that can be used to degrade the androgen receptor (AR). The discovery is a turning point, and since then, the research on PROTAC targets started thriving.

Professor Crews established Arvinas in 2013 to promote the small molecule PROTAC technology to the clinic. After the Arvinas, upstart companies were established, all dedicated to exploring the therapeutic potential of small molecule protein degradants. In 2019, Arvinas' AR-targeted oral small molecule PROTAC ARV-110 became the first protein degrading agent to enter clinical trials, which is another milestone in this field, and represents a key step forward for PROTAC technology to become a medicine. Soon after, Arvinas' small molecule PROTAC (ARV-471) targeting ER also entered the clinic.

The popularity of the PROTAC rises continuously. In addition to more and more start-up companies, pharmaceutical giants revealed great enthusiasm for PROTAC technology. There are dozens of CROs in the United States that have mastered PROTAC molecule development technology, such as Creative Biolabs.

The much attention PROTAC received results from its unique advantages.

* High selectivity. This type of protein degrading agent relies on the triple action between the target-PROTAC-E3 enzyme. In the human proteome, there are an estimated 600 E3 ligases, of which each has a unique cell expression profile.

* More targets. PROTAC only needs to weakly bind to the target protein to specifically label it via transient binding events instead of occupancy-based strong binding like traditional small molecule inhibitors. Also because of this, PROTAC is expected to target previously considered undruggable targets.

* Versatility. Since traditional small molecules only block the active part of the target protein, but the protein degrading agent based on PROTAC technology will destroy all the functions of the target protein, including the scaffold function.

Thousands of PROTAC molecules have been developed after more than 10 years of exploration and accumulation. According to the latest report from Nature, by the end of this year, at least 15 protein degradation agents (PROTAC and molecular glue) will be tested in patients.

Popular targets: AR, BTK

AR is one of the most popular targets and the first PROTAC target to enter the clinic. The reason why many companies and institutions choose AR is that AR is a verified target, and many drugs have been approved for marketing, including Flutamide that was approved for marketing as early as 1989, and Enzalutamide, which entered the market later. The second reason is that patients will develop resistance to existing AR inhibitors, which can be overcome by AR degradants.

BTK is another popular proven target. The FDA approved the first BTK inhibitor (Ibrutinib) in 2013, of which sales reached nearly 10 billion USD last year. BTK-PROTAC is also expected to solve the problem of resistance.

Difficult targets: IRAK4, BRD9

Some protein degradation agents targeting difficult drug targets are also under development, such as IRAK4, a kinase that activates IL-1 family receptors and Toll-like receptors (TLRs) inflammatory signals. Although IRAK4 is related to various diseases like arthritis, atherosclerosis, Alzheimer's disease, gout, systemic lupus erythematosus, the development of small molecule drugs targeting IRAK4 has made progress in recent days.

BRD9 is a member of the bromodomain family of proteins. Proteins containing bromodomains can recognize acetylated lysines on histones and other proteins. In the past 10 years, they have attracted considerable attention in the industry because of their drug-ready properties and a series of biological functions, including as epigenetic readers. Some new findings reveal that BRD9 has a key role in a rare sarcoma, which may be driven by its scaffold function, and the exact biological principles are still being studied. Although small molecules can bind and inhibit the bromine domain of BRD9 with high selectivity, the use of BRD9 inhibitors to kill cancer cells has not achieved good results. A paper published in 2018 showed that BRD9 degradants can prevent tumor progression in a mouse model of synovial sarcoma.