The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents

Abstract

The induction of protein degradation in a highly selective and efficient way by means of druggable molecules is known as targeted protein degradation (TPD). TPD emerged in the literature as a revolutionary idea: a heterobifunctional chimera with the capacity of creating an interaction between a protein of interest (POI) and a E3 ubiquitin ligase will induce a process of events in the POI, including ubiquitination, targeting to the proteasome, proteolysis and functional silencing, acting as a sort of degradative knockdown. With this programmed protein degradation, toxic and disease-causing proteins could be depleted from cells with potentially effective low drug doses. The proof-of-principle validation of this hypothesis in many studies has made the TPD strategy become a new attractive paradigm for the development of therapies for the treatment of multiple unmet diseases. Indeed, since the initial protacs (Proteolysis targeting chimeras) were posited in the 2000s, the TPD field has expanded extraordinarily, developing innovative chemistry and exploiting multiple degradation approaches. In this article, we review the breakthroughs and recent novel concepts in this highly active discipline.

Opportunities and challenges in translational science

“…Despite these new technologies, a large number of disease‐causing abnormalities remain inaccessible, including those caused by aberrant protein‐protein interactions, missense mutations causing misfolding, and nonsense and splice‐site mutations. New types of chemistries (e.g., peptoids 41 and protacs 42 ) and new genetic therapy modalities including modified anti‐sense oligonucleotides (ASOs) and morpholinos, CRISPR‐Cas9, and other somatic cell gene editing technologies, 43 and more targeted and immune‐evading gene therapy viral and nonviral vectors are all needed areas of translational science innovation. In addition, for the new gene therapy, gene editing and cell therapies to reach their potential as widespread and accessible treatments, scale‐up, manufacturing, reproducibility, impurity, qualification, and other limitations typically referred to as “Chemistry, Manufacturing, and Controls” (CMC) will need to be overcome.…”

Inhibitors of Cyclin-Dependent Kinases: Types and Their Mechanism of Action

“…It is anticipated that, by using this method, toxic and disease-causing proteins could be depleted from cells under the potentially effective low-dose treatment. Small molecules able to induce degradation of target proteins can be divided into three major classes based on the structure of the compounds and their mechanism of action [ 123 ]. Single-ligand molecules able to create a direct interaction with the target protein to induce degradation belong to the first class of compounds.…”

Emerging protein degradation strategies: expanding the scope to extracellular and membrane proteins

“…LYTAC provides possibilities to change protein ligands into degraders. TPD strategy possesses kinetic advantages by binding to any “nook” or “cranny” on POIs with low dose 91 , 92 . Generally, ligands that bind to the desired targets but were set aside because they could not adequately block protein function may be possible to be permitted as warheads of LYTAC.…”