To solve "non-drugable" and "resistance", Nature summarizes the four major trends in the development of PROTAC!

In the context of the increasing popularity of macromolecular drugs such as monoclonal antibodies, double antibodies, and ADCs, small molecule drugs have once again become the focus through the breakthrough new technology of PROTAC
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After 20 years of development, PROTAC technology has attracted the attention of many pharmaceutical companies, such as Pfizer, Bayer, Novartis and other multinational pharmaceutical companies; Hengrui Medicine, BeiGene, Haisco and other domestic pharmaceutical companies also have layouts
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Recently, one of the co-founders of Arvinas, a star company in the PROTAC field, Professor Craig M.
Crews of Yale University and his partners jointly published a review on Nature Reviews Drug Discovery, summarizing the development of PROTAC in the first 20 years, and discussing the next 20 years.
Four major development directions of PROTAC in 2018
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Many targets that play key roles in cancer and other diseases are notoriously difficult to drug, some of which are difficult to bridge with small molecules due to their wide and shallow active sites; others have "smooth" surfaces with few small molecules A site where a molecule can bind
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But with the continuous development of PROTAC technology, these undruggable targets have also become within reach
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Protein degradation targeting chimera technology (PROTAC) is to use hybrid bifunctional small molecule compounds to bring the target protein and intracellular E3 ubiquitin ligase closer, and use the ubiquitin-proteasome protein degradation pathway in vivo to specifically degrade the target protein
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The drug consists of 3 parts, that is, one end is the specific E3 ubiquitin ligase ligand, the other end is the specific ligand of the target protein and the linker in the middle, thus forming the "target protein-PROTAC-E3 ubiquitin ligase"
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Different from traditional small molecule drugs, PROTAC drugs do not need to bind tightly and for a long time to the pathogenic target to degrade the pathogenic target
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By destroying, rather than inhibiting, protein targets, problems of non-druggability and drug resistance are solved
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Compared with the current main drug development technology, it has the following characteristics: In 1999, researchers from Proteinix Company submitted a patent application for the use of small molecular compounds to degrade specific proteins based on the ubiquitin mechanism
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Two years later, Craig Crews of Yale University and Raymond Joseph Deshaies of Caltech reported in a 2001 PNAS paper on peptide-based bifunctional small molecules Induced metaP-2 protein degradation, and formally proposed the concept of PROTAC
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However, the first generation of PROTACs failed due to the difficulty of peptide compounds entering cells
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Until 2008, the Crews team designed the second-generation PROTACs that can be used to degrade androgen receptor (AR) based on the E3 ubiquitin protein ligase MDM2
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In 2015, the Crews team designed a new generation of PROTACs based on the novel E3 ubiquitin ligase VHL and CRBN ligands, which reduced the levels of various proteins by more than 90%
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In the past few years, PROTAC technology has basically matured
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The authors propose that the next milestones in the PROTAC field will focus on the following four areas, namely, identifying the best protein degradation targets; expanding the scope of clinical application of E3 ligases; expanding the scope of clinical treatment to diseases beyond oncology; Develop other PROTAC modes
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1.
Identify the best protein degradation targets The first wave of clinical-stage protein degradation agents selected mature targets that have been clinically validated
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Targeted products have been developed with moderate success, and the potential of PROTACs as a therapeutic modality has been validated
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However, the real promise of the technology is in enabling those undruggable targets
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The article proposes "principles of PROTAC targets" (see figure below), including: changes from the natural state through overexpression, mutation, aggregation, isoform expression or fine localization, resulting in disease in a gain-of-function manner; A binding surface accessible to E3 ligases; ideally, a structure-free region capable of accessing the proteasome
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Proteins mutated for resistance to targeted therapy, proteins with backbone functions, and proteins that are "undruggable" by other therapeutic modalities may also be suitable PROTAC targets
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2.
Expand the clinical application of E3 ligases The human genome encodes more than 600 E3 ubiquitin ligases, but only a few E3 ligases (VHL, CRBN, etc.
) are currently used for PROTAC design.
How to expand the available E3 ligases for PROTAC The technical E3 ubiquitin ligase is also one of the challenges faced by PROTAC
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The authors propose that new E3 ligases can be found in the following ways
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A practical and valuable approach is to find broadly applicable, ubiquitous ligases, similar to CRBN and VHL
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They can be paired with any target protein, allowing unrestricted application in multiple therapeutic indications
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Another approach, based on key characteristics of ligases, such as tissue and cell specificity, tumor enrichment, and tumor necessity, could provide development opportunities for domain-specific protein degradation therapies
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Interestingly, some ligases exhibit "reverse specificity" (low expression in specific tissues or cell types), which may also present opportunities for protein degraders
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In addition, another new frontier in precise targeting of protein degradation is PROTAC molecules that specifically target tumor cells, which can be achieved by targeting tumor-specific or tumor-enriched E3 ligases
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3.
Extending the scope of clinical treatment to diseases beyond oncology So far, research on protein degraders has mainly focused on the field of tumors, but since protein degraders may degrade any chosen target, their application can be broader
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In fact, in recent years, protein degraders have gradually been used in fields other than oncology, such as neurodegenerative diseases, inflammation/immunology, and breakthroughs have been made
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Following the success of immune checkpoint inhibitors, the development of small-molecule drugs capable of eliciting anticancer immune responses is an important area of ​​drug development
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PROTAC molecules have the potential to activate immune cells in the mode of small molecule drugs, mimic the effects of PD-1/PD-L1 targeted therapy, and become a potential "first-in-class" therapy
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Recently, PROTAC molecules targeting MAP4K1 have shown promising preclinical activity
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One of the key features of PROTAC molecules is their ability to degrade proteins that are not targeted by traditional small-molecule inhibitors because they lack an active site
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This feature makes proteins that accumulate in various neurodegenerative diseases, such as Tau, a potential target
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4.
Development of other PROTAC modalities In addition to PROTAC, various novel protein degradation technologies have been developed, further expanding the range of targets that can be targeted by this technology
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The authors define three types of PROTACs: traditional small-molecule PROTACs, peptides or other biological PROTACs (bioPROTACs), and PROTACs (hybrid PROTACs) that contain both peptides and traditional small-molecule "warheads"
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bioPROTACs are based on gene encoding to directly fuse peptides, fusion proteins, and oligonucleotides with E3 ligases, which bind and degrade target proteins through peptide or protein recognition domains
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Since BioPROTAC relies on genetic coding, there are certain limitations
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