Development Trends And Potential Challenges of PROTACs

PROTAC technology has been in development for more than 20 years. PROTAC proof-of-concept studies date back to 2001, when Crews' team tested the possibility of artificially induced intracellular protein degradation with a peptide that was too large in molecular weight and required cells to penetrate the peptide to improve cell permeability. The discovery of the first small molecule PROTAC and the subsequent small molecule E3 ligand, reported in 2008, greatly promoted the pursuit of PROTAC technology in academia and industry.

The Development Trend of PROTAC

Verify the degradation of "non-druggable proteins" in clinical trials: At present, PROTAC molecules that have entered the clinical trial stage mainly target traditional AR, ER, BTK, etc. Kymera Therapeutics' KT-333 targeting STAT3 and Astellas Pharma's ASP3082 targeting KRAS G12D are in phase I clinical trials, and we expect satisfactory results from PROTAC molecules on such difficult-to-drug targets.

Specific targeting: The reported targeting strategies such as antibody-PROTAC conjugates can effectively improve the recognition of PROTAC molecules on tumors; PROTACs are activated by light, folic acid or reactive oxygen species in tumors through modification groups, which is also an effective way to reduce the potential toxicity of systemic delivery of PROTAC molecules.

Exploring other indications: Currently, the indications of PROTACs are still concentrated in the field of tumors. Actively exploring other proteins of PROTAC in indications such as IRAK4 and other autoimmune diseases will help to develop broader application prospects of this technology.

Potential challenges for PROTAC

Although PROTAC has shown positive results in both preclinical and clinical trials, the technology may face the following challenges as its application progresses.

Drug resistance: There have been limited reports of drug resistance caused by PROTACs in preclinical trials, but this possibility warrants vigilance. At present, a large number of PROTAC molecules induce the degradation of target proteins through the ubiquitin-proteasome pathway, including the inactivation of E3 ligase and E2 conjugating enzymes, which may directly affect the regulation of PROTAC on the level of target proteins. There is a need to assess whether long-term use of PROTACs in patients in clinical settings leads to drug resistance.

Limited application scenarios: Since PROTAC needs to enter the cell and bind to the target protein and E3 ligase at the same time, this mechanism of action limits the application of this technology to cell membrane proteins and extracellular proteins.

In the past 20 years, PROTAC has gone through a long journey from the laboratory to the clinic, and it has only been 4 years since it entered the clinic. At present, the preliminary clinical data of PROTAC technology is satisfactory, and it is expected that this technology will bring substantial hope and help to more disease patients.

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