Undoubtedly, proteolysis targeting chimera (PROTAC) technology stands as a revolutionary approach in drug development. By leveraging the ubiquitin-proteasome system to degrade target proteins, this technology has redefined the landscape of drug discovery and treatment. Despite its remarkable strides, PROTAC encounters a challenge in the form of non-tumor toxicity in healthy cells. This issue hinders the clinical feasibility of targeted cancer therapies.
Elevating Selective Degradation:
At present, scientists are actively exploring strategies to augment cell-selective degradation and reduce the associated side effects. It has been found that PROTAC predrug strategies can facilitate the precise release of active PROTAC into tumors and minimise targeted extra-tissue toxicity, further expanding the range of potential applications of PROTAC technology in drug development.
A Novel Approach:
In this pursuit, a groundbreaking advancement has emerged from Wei Wang's team at the University of Arizona. Their innovation centers on targeted activation of PROTAC through bioorthogonal click chemistry. By integrating TCO-modified PROTAC prodrugs with ligands of VHL E3 ubiquitin ligases via bioorthogonal trans-cyclooctene (TCO) moieties, and employing tetrazine (Tz)-modified RGD peptides (c(RGDyK)-Tz) to target integrin αvβ3 in cancer cells, they achieve the controlled release of PROTAC precursors. This orchestrated process leads to the recruitment of endogenous VHL E3 ubiquitin ligases for the degradation of POIs (Proteins of Interest) within the proteasome, culminating in targeted degradation of POIs exclusively in cancer cells.
The remarkable findings of this study have recently been unveiled in the Journal of the American Chemical Society.
Synthesizing Selective Prodrugs:
The researchers embarked on synthesizing prodrug molecules TCO-ARV-771 and TCO-DT2216 by strategically incorporating a trans-cyclooctene (TCO) moiety into the PROTAC molecules (ARV-771 and DT2216) designed for protein degradation. Concurrently, their focus on αvβ3 integrins, known for their specific overexpression on cancer cell surfaces, led to the creation of c(RGDyK)-TCO-ARV-771 and c(RGDyK)-Tz compounds. The stability of these compounds was confirmed for a click reaction within a mere 3 hours. Moreover, c(RGDyK)-Tz exhibited remarkable efficiency in selectively delivering PROTAC to αvβ3 integrin-overexpressing tumor cells. The bioorthogonal activation of TCO-ARV771 using c(RGDyK)-Tz facilitated BRD4 degradation in HeLa cells, mirroring the ubiquitin-proteasome pathway-mediated protein degradation via ARV-771.
Innovative Bioorthogonal Control:
This pioneering bioorthogonal control prodrug strategy sets a new paradigm in selectively managing PROTAC's degradation activity within cancer cells. Unlike traditional PROTAC prodrugs reliant on cancer biomarkers or the tumor microenvironment for activation, this innovative bio-orthogonal approach achieves on-demand PROTAC activation and release at the tumor site. The result is a remarkable reduction in premature drug activation and a remarkable step toward improved bioavailability and reduced toxicity.
The ongoing development of PROTAC technology, underscored by strategic innovations like the bioorthogonal control prodrug strategy, promises to reshape the future of cancer therapy. As researchers continue to refine and expand these approaches, the prospect of more effective and targeted treatments for cancer comes closer to reality.