Traditional drug development strategies focus on how to treat diseases by directly regulating the activity of proteins or enzymes. Therefore, the development and application of protein activity regulators, especially inhibitors, has always been the mainstream of drug R&D. However, traditional small molecule and antibody drugs can only target about 20% of the protein, while the newly emerging degradation technology may crack the remaining 80% of the proteome, which is another emerging direction and strategy in the field of drug R&D following protein kinase inhibitors and monoclonal antibodies (mAb), excavating neo approaches to supporting research and development of drugs against difficult diseases.
The small molecule degrading agent degrades the target protein by mediating the recognition of the ubiquitinated ligase and the target protein. At present, there are two main types of protein degrading agents. One is PROTAC ( https://www.creative-biolabs.com/protac/ ) that specifically degrades target proteins through the ubiquitin-proteasome pathway, the other is molecular glue, which also binds to ubiquitinated ligase, but unlike PROTAC, recognizes and degrades new substrates by modifying the surface of ubiquitinated ligase.
Now, many large pharmaceutical companies are investing in small molecules degradation agents. Dozens of biotechnology companies ( https://www.creative-biolabs.com/protac/ ) are exploring this new technology. Academic groups are also developing degradants that can be used clinically. A PROTAC tracking database now lists more than 1,600 publicly disclosed heterologous functional degradation agents that can act on over 100 targets.
At present, a variety of targeted protein degradation agents have entered clinical trials. At the same time, pharmaceutical companies are working hard to advance multiple pre-clinical projects to the clinic. Many drugs have proven therapeutic utility to degrade targets, and their efficacy, safety, and commercial risks have been understood. Some developers are also researching new targets.
Select the target wisely.
Arvinas, established in 2013, was one of the first companies to enter the field of degradants, for which selecting the target wisely is the key to determining project priorities. The androgen receptor (AR) is one of Arvinas' core research targets. Anti-androgen therapies to prevent AR signaling include flutamide that was first marketed in 1989, and enzalutamide, which was approved in 2012 and now has annual sales of $3 billion.
The main selling point of degradants is their ability to drive the destruction of proteins with multiple functions. Proteins with catalytically active sites (including kinases) can also be used as scaffold proteins (proteins with multiple protein binding domains that can organize proteins related to the signal transduction pathway into groups), such as keeping protein complexes together. This property hinders many drug development projects. Taking IRAK4 as an example, which can simultaneously activate IL-1 family receptors and Toll-like receptor (TLR) inflammatory signals. Although it is related to arthritis , atherosclerosis, Alzheimer's disease, gout, systemic lupus erythematosus, psoriasis, etc., drug developers only made progress recently with small molecules targeting IRAK4. One possible explanation is that the protein has a scaffold function that binds Myddosome complexes together and promotes downstream inflammatory signal transduction even if its kinase function is blocked.
Molecular gel degradation agent can be a breakthrough.
Most small molecules rely on the interaction of ligands and proteins to gain activity, while molecular gel degradation agents capture their targets by regulating the protein-protein interface. Both Ikaros and Aiolos are zinc finger transcription factors, which are difficult to target for small molecule drugs due to the lack of catalytically active sites. Molecular gel degradation agents can act on new targets, including targets that cannot be reached by heterobifunctional degradation agents.
By the end of this year, at least 15 targeted degradants involving heterobifunctional protein cleavage targeted chimera (PROTAC) to molecular gel should enter the clinical trial stage.
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