Generation and characterization of PROTAC strategy as a new anticancer therapy

Among all the elements of the human proteome there are several disease-relevant proteins still difficult to treat through a traditional approach based on the use of inhibitory drugs, which act with an occupancy-driven pharmacology. Attempting to overcome these limitations, the strategy of "Targeted protein degradation" (TPD) represents a promising and alternative pharmacological approach, recently emerged as a relevant biological tool in the field of chemical biology and drug discovery, to precisely control the concentrations of pathogenic proteins at a post-translational level, inducing their specific degradation. The most important current approach based on this strategy, first reported in 2001, is known as PROTAC (PROteolysis-TArgeting Chimera) technology. The PROTAC mode allows to exploit the Ubiquitin-proteasome cellular system (UPS), through the tailor-made design of heterobifunctional small molecules, capable of degrading a target protein, favoring its ubiquitination. In this regard, several studies have been performed to develop better degraders, capable of functioning both as a biological tool in basic research, and as a new emerging therapeutic modality in the field of precision medicine. In particular, in 2018, at the Dana-Farber Cancer Institute it has been conceived by Nabet et al. the so-called dTAG system, a chemical biological tool used to validate in vitro and in vivo the functionality of a PROTAC molecule still under development. Moreover, in the oncology field this pharmacological strategy could have important therapeutic implications. An example of this opportunity is represented by two very interesting works that explored the applicability of the PROTAC system for the degradation of different enzymatic components of the MAP Kinase pathway: KRASG12C, a specific mutated oncogenic protein, which for many years since its discovery has been considered undruggable and only recently new powerful inhibitory drugs have been able to attack it, and the mutated isoforms of the BRAF protein, in this case a target already treatable pharmacologically but for which resistance mechanisms inevitably emerge. Although it is a field still in full development, the Targeted Protein Degradation method can represent an important pharmacological alternative tool to those currently present, which allows to act from another point of view and in a more efficient way against the mechanisms of drug-induced resistance, to degrade proteins until now considered "undruggable" and to decipher pathological mechanisms still not entirely clear.