Protein degradation technology: a strategic paradigm shift in drug discovery

Abstract

Targeting pathogenic proteins with small-molecule inhibitors (SMIs) has become a widely used strategy for treating malignant tumors. However, most intracellular proteins have been proven to be undruggable due to a lack of active sites, leading to a significant challenge in the design and development of SMIs. In recent years, the proteolysis-targeting chimeric technology and related emerging degradation technologies have provided additional approaches for targeting these undruggable proteins. These degradation technologies show a tendency of superiority over SMIs, including the rapid and continuous target consumption as well as the stronger pharmacological effects, being a hot topic in current research. This review mainly focuses on summarizing the development of protein degradation technologies in recent years. Their advantages, potential applications, and limitations are also discussed. We hope this review would shed light on the design, discovery, and clinical application of drugs associated with these degradation technologies.

Pathobiology and Therapeutic Relevance of GSK-3 in Chronic Hematological Malignancies

“…Another benefit of using this technology is that one PROTAC molecule is capable of inducing multiple rounds of degradation; hence, therapy requires less drug exposure. Therefore, in general, PROTACs display a lower toxicity in comparison to conventional inhibitors, although there are still unresolved issues including a relatively high molecular weight and potential off-target activity [ 207 ]. Third generation, light switchable PROTACs are now being developed to limit the problem of uncontrolled protein degradation in any cells in an organism [ 208 ].…”

Role of BAG5 in Protein Quality Control: Double-Edged Sword?

“…Additionally, chaperones and co-chaperones help in the removal and recycling of misfolded protein by cellular protein degradation systems. Most of the cellular protein gets degraded through the ubiquitin-proteasome system (UPS) ( Sun-Wang et al, 2020 ; Li et al, 2021 ). The cell also uses a vesicle-mediated protein degradation system called autophagy to degrade cellular proteins and subcellular organelles ( Delbridge et al, 2017 ).…”

“…However, genetic mutation, hemodynamic stress, cellular toxicity, and cellular infection change cellular proteostasis and dysregulate a quintessential environment required for normal cellular metabolism. Impairment of cellular PQC and accumulation of protein aggregates with faulty subcellular organelles leads to the generation of oxidative stress, inflammation, and cell death ( Li et al, 2021 ). These modifications are known to be associated with the impairment of several organ functions and the development of several life-threatening diseases including, CVD, neurological disorders, and premature aging ( Gong et al, 2016 ; Kaur et al, 2020 ).…”

Molecular glues: The adhesive connecting targeted protein degradation to the clinic

“…This approach is emerging as a novel therapeutic method to aim at diseases such as cancer, inflammatory and immune diseases and infections, as many of them are driven by the aberrant expression of a pathogenic protein. [1][2][3][4][5] TPD involves recruiting disease-causing proteins previously thought to be "undruggable" due to their lack of canonical ligand binding sites for rapid destruction and elimination via the ubiquitin-proteasome pathway. The ubiquitin-proteasome system (UPS) is a major mechanism for cellular protein degradation and maintaining protein homeostasis, as part of the regular cellular housekeeping processes.…”

“…52 These compounds promote the ubiquitination of β-catenin by β- (FKBP12) protein degradation, etc. 4 Recently, a new approach has been applied to a challenging target class -the intrinsically disordered proteins. It involves forcing disordered proteins to acquire a druggable interface using molecular glues to stabilize their interaction with 14-3-3 adaptor proteins, a signaling hub for critical cell processes.…”