The wide range of application and the great potential in overcoming drug resistance and targeting non-proprietary targets, research and development in PROTAC field has been hot in recent years.
PROTAC, protein degradation targeted chimera technology, uses heterozygous bifunctional small molecular compounds to pull the target protein closer to the E3 ubiquitin ligase in the cell, and specifically degrades the target protein through the ubiquitin-proteasome protein degradation pathway. Compared with traditional small molecular drugs, PROTAC can achieve protein degradation rather than protein functional inhibition, and can target more drug targets such as scaffold proteins and undruggable proteins. It does not depend on the binding of active sites of targets, so it is easy to develop highly selective drugs, and retains the characteristics that small molecular drugs target intracellular targets and deliver drugs in a variety of ways.
At present, the global PROTAC-based drug R&D is flourishing, and the PROTAC molecules targeting AR, ER, BTK, BRD9, IRAK4, and others have entered clinical development. According to the report published in Nature Reviews Drug Discovery in July 2021, more than 1,000 proteins can be used as potential targets for PROTAC, providing new opportunities for PROTAC-based drug development.
At present, pharmaceutical giants are aiming at this field. In July this year, Pfizer reached an agreement with PROTAC star company Arvinas for more than $2 billion to jointly develop and promote its oral PROTAC protein degradation agent targeting estrogen receptor (ER), which is currently in phase II clinical trials. At the same time, Roche, Bayer, Merck, GSK, Novartis, AstraZeneca, BMS, and so on have also laid out PRORAC.
In spite of multiple advantages, PROTAC drug development still faces technical difficulties, such as high molecular weight, poor water solubility-membrane permeability, low bioavailability, synthesis difficulty, and so on.
There are more than 600 kinds of E3 ligase in cells, but now the drug design mainly focuses on VHL and CRBN, which will result in drug resistance and toxicity caused by degradation of neo-substrate, so developing new E3 ligase is one of the research directions. Based on the selection of POI and E3, how to select the appropriate ligand and linker for PROTAC will also affect the spatial conformation of the ternary complex, and further affect its stability and degradation efficiency. The synergistic effect, safety, and selectivity of target protein and E3 ligase linked by PROTAC also need to be considered.
PROTAC depends on UPS (ubiquitin-proteasome system) to degrade target proteins, and has unique advantages over small molecular inhibitors and antibody drugs. The development of PROTAC drugs first needs to verify its effective degradation of the target. In later stages, a series of in vitro and in vivo experiments need to base upon the effective degradation of the target. In addition, different PROTAC projects have diverse points of focus, such as synergistic effect, the possibility of neosubstrate degradation, and whether neosubstrate degradation will bring toxicity or other phenotypes. Recently, it has been reported that trivalent PROTAC increases the efficiency of protein degradation by 300 times by binding to three protein sites. Therefore, in vitro studies should be based on the full understanding of the target, project, and PROTAC itself.