Protein Precision: “Harnessing Targeted Protein Degradation”

Proteins are the chains of amino acids linked together in different combinations and perform a wide variety of functions. These are the vital structural component of cells, which help in cell functioning and regulation of building body tissues. However, continuous regulation of the cellular proteome is essential for maintaining the right balance of different proteins necessary for normal cellular function, survival, and proliferation. Proteins are continuously degraded intracellularly or extracellularly to maintain equilibrium inside the cell, commonly termed protein homeostasis. The Targeted Protein Degraders Industry growing at an annualized rate (CAGR) of 32% during the forecast period 2024-2035.

The ubiquitin-proteasome system is one of the key regulatory mechanisms involved in controlling protein degradation and turnover. Due to its involvement in multiple metabolic and regulatory functions, the ubiquitin-proteasome system is considered as a vital part of the cellular machinery, controlling protein homeostasis. Several clinical conditions, especially cancer, are often associated with abnormal protein functioning caused due to mutations and uncontrolled cell division. Moreover, protein misfolding have been known to result in various neurodegenerative disorders, such as Parkinson, Huntington, and Alzheimer’s disease.

Extensive research on the role of protein homeostasis in these disease conditions has paved the way for development of the small molecules that can target various components of UPS to enable efficient degradation of proteins. Specific inhibitors, which bind to disease-associated proteins and prevent them from functioning abnormally, have demonstrated remarkable therapeutic potential in such diseases. However, these inhibitors are unable to bind to several potential targets, such as scaffolding proteins, transcription factors and other non-enzymatic proteins, owing to their intracellular location and absence of suitable binding pockets.

Therefore, small molecule degraders have been used to selectively induce the degradation of a variety of pathogenic proteins as an alternative approach. Small-molecule-induced protein degradation is emerging as a potential strategy for targeted degradation of a broad range of proteins. It involves simultaneous binding of a small molecule to a protein of interest and an E3 ligase leading to a catalytic ternary complex that drives protein ubiquitination and subsequent proteasomal degradation. The following figure presents some of the advantages offered by targeted protein degraders.

Advantages Offered by Targeted Protein Degraders

The promise of induced protein degradation as a novel therapeutic modality has attracted considerable attention in the pharmaceutical industry. Due to which, several big pharma companies and other industry stakeholders are actively contributing towards development of protein degradation therapies and technologies, contributing towards growth of targeted protein degradation market.
Some of the key players engaged in the targeted protein degradation market include Arvinas, Kymera Therapeutics, Monte Rosa Therapeutics and Lycia Therapeutics.

Overview of Targeted Protein Degradation

Protein degradation plays a vital role in maintaining protein equilibrium in the human body. In general, small molecule inhibitors, antisense oligonucleotides and monoclonal antibodies were utilized for protein degradation that binds to the specific pathogenic proteins to hinder their activity to obtain therapeutic results. However, the existing inhibitors bind to constricted pathogenic agents, comprising less than 20% of all disease-causing proteins, leaving 80% of them as undruggable targets. This limitation has paved the way for the development of targeted protein degradation approaches. Targeted protein degradation is a novel drug discovery approach that leads to destruction of disease-causing proteins by hijacking cellular machinery within the small molecules. This modality responsible for degradation of proteins is known as protein degraders. Protein degraders are bifunctional small molecules that recruit E3 ubiquitin ligases to the protein of interest and mediate its ubiquitination and subsequent proteolysis by the proteasome.

There are various types of targeted protein degraders that are being investigated in different stages of development. These include degraders, such as Proteolysis Targeting Chimeras (PROTACS), Endosome Targeting Chimeras (ENDTACS), Photochemically Targeted Chimeras (PHOTACS), Hydrophobic Tags, Immunomodulatory Imide Drugs (IMIDS), molecular glues, Selective Hormone Receptor Degraders (SHRDS), Specific And Nongenetic Inhibitor-of-Apoptosis Proteins (IAP)-Dependent Protein Erasers (SNIPERS), Deubiquitinase (DUB) inhibitors, degronimids, intracellular click-formed proteolysis-targeting chimeras (CLIPTACs), semiconducting polymer nano-PROTAC (SPNpro), floate-PROTAC, antibody-PROTAC conjugates and antibody-based PROTACs (AbTACs), lysosome-targeting chimera (LYTACs), ribonuclease targeting chimeras (RIBOTACs), transcription factor-PROTAC (TF-PROTAC), chaperone-mediated protein degradation (CHAMP), biological PROTACs (bioPROTACs), specific bromodomain and extra-terminal domain (BET) degraders.

Targeted Protein Degraders Industry Pathway

There are numerous pathways by which protein substrates can be targeted, such as the unfolded protein response degradation (UPR), endoplasmic-reticulum-associated protein degradation (ERAD) and ubiquitin-proteasome system pathways, which exist within a cell. It is worth mentioning that the ubiquitin-proteasome system pathway is one of the key mechanisms that control protein function and stability. The ubiquitin proteasome system pathway is a highly conserved pathway found in all eukaryotes, starting from yeasts to mammals. In the eukaryotic cell, the UPP is essential for the targeted degradation of most short-lived proteins. This system plays a central role in cell proliferation, transcriptional regulation, apoptosis, immunity and development. The pathway consists of multiple classes of regulatory enzymes and substrates that facilitate the process of protein degradation.

Therapeutic Areas Targeted Protein Degraders Industry

Targeted protein degrader’s ability to hijack cell’s natural machinery has paved the way for the utilization of these degraders across diverse range of therapeutic areas. Currently, several targeted protein degradation companies are evaluating targeted protein degraders for various oncological conditions, such as breast cancer, prostate cancer and multiple myeloma and non-oncological conditions. The following figure presents the various therapeutic areas targeted by degraders, being developed by targeted protein degradation companies.

Targeted protein degrader therapeutics area

Benefits Offered by Targeted Protein Degraders Industry

Protein degraders target selective proteins, reducing their impact on non-disease-related proteins and offering high specificity. This is primarily due to the fact that these degraders do not require an active site for destruction of proteins and can selectively kill them by altering their cellular machinery. In addition, these degraders can help in optimizing linker length and in stabilization of ternary complexes. As compared to existing small molecule inhibitors, targeted protein degradation offers broad applicability and can overcome resistance. This allows targeted protein degradation approaches to target “undruggable” proteins, such as transcription factors, non-enzymatic proteins and scaffolding proteins, widening the scope for the clinical development of next generation therapeutic modalities. Moreover, a single protein degrader has the ability to potentially eliminate multiple disease-causing proteins through proteasome degradation of the target protein.

However, an inhibitor drug can only block a single disease-causing protein at a time. Further, the efforts of various targeted protein degradation technology companies in development of different targeted protein degradation technologies allows personalization for different targets leading to the development of novel therapeutic drugs that enhance versatility in various treatment strategies. Owing to various advantages offered by targeted protein degradation therapeutics, there has been a considerable rise in the interest of both the pharmaceutical industry and academia players to develop and commercialize targeted protein degraders, contributing towards growth opportunities for targeted protein degradation market.

Future Perspectives

Targeted protein degradation has revolutionized the field of protein degradation and protein homeostasis by offering several advanced protein degraders and treatment options. Despite all the advantages, there are certain challenges that are important to overcome in order to drive substantial growth within the targeted protein degradation market. One of the primary requirements is to expand the range of proteins that can be targeted for degradation, improving the applicability of this approach across various therapeutic areas.

In addition, integration of targeted protein degradation with traditional drugs can offer a comprehensive approach to enhancing treatment outcomes. However, a clear understanding of degradation pathways and potential side-effects is crucial. It is worth noting that technological advancements in degrader molecule design, such as increased cell permeability, solubility, absorption and low molecular weight along with improved delivery mechanisms are likely to enhance the efficiency and specificity of targeted protein degradation. In addition, less than 2% of the E3 ligases are available for degradation, presenting an opportunity for the discovery of novel and advanced E3 ligases that can help in shaping the landscape of targeted protein degradation.

Further, continued progress in clinical trials can lead to approval of targeted protein degradation-based therapies paving the way for their integration into standard medical practices. Currently, North America captures the largest share of targeted protein degradation market. Numerous factors contribute to the region’s dominance in this industry, which include the presence of several well-established drug developers with extensive manufacturing capabilities in the region. However, with increased approvals and understanding of protein degradation pathways, the targeted protein degradation market can witness substantial market growth in other regions as well. Considering the aforementioned factors, the targeted protein degradation market is poised to have a promising future during the forecast period.

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