Small-molecule drug discovery has traditionally focused on occupancy of a binding site that directly affects protein function, which typically precludes targeting proteins that lack such amenable sites. Furthermore, high systemic drug exposures may be needed to maintain sufficient target inhibition in vivo, increasing the risk of undesirable off-target effects. Induced protein degradation is an alternative approach that is ‘event-driven’: upon drug binding, the target protein is tagged for elimination. Emerging technologies based on proteolysis-targeting chimeras (PROTACs) that exploit cellular quality control machinery to selectively degrade target proteins are attracting considerable attention in the pharmaceutical industry owing to the advantages they could offer over traditional small-molecule strategies. These advantages include the potential to reduce systemic drug exposure, the ability to counteract increased target protein expression that often accompanies inhibition of protein function and the potential ability to target proteins that are not currently therapeutically tractable, such as transcription factors, scaffolding and regulatory proteins.

Proteolysis Targeting Chimera (PROTAC) technology is a rapidly emerging alternative therapeutic strategy with the potential to address many of the challenges currently faced in modern drug development programs. PROTAC technology employs small molecules that recruit target proteins for ubiquitination and removal by the proteasome. The synthesis of PROTAC compounds that mediate the degradation of c-ABL and BCR-ABL by recruiting either Cereblon or Von Hippel Lindau E3 ligases is reported. During the course of their development, we discovered that the capacity of a PROTAC to induce degradation involves more than just target binding: the identity of the inhibitor warhead and the recruited E3 ligase largely determine the degradation profiles of the compounds; thus, as a starting point for PROTAC development, both the target ligand and the recruited E3 ligase should be varied to rapidly generate a PROTAC with the desired degradation profile.

Proteolysis targeting chimera (PROTAC) technology has emerged over the last two decades as a powerful tool for targeted degradation of endogenous proteins. Herein we describe the development of PROTACs for receptor tyrosine kinases, a protein family yet to be targeted for induced protein degradation. The use of VHL-recruiting PROTACs against this protein family reveals several advantages of degradation over inhibition alone: direct comparisons of fully functional, target-degrading PROTACs with target-inhibiting variants that contain an inactivated E3 ligase-recruiting ligand show that degradation leads to more potent inhibition of cell proliferation and a more durable and sustained downstream signaling response, and thus addresses the kinome rewiring challenge seen with many receptor tyrosine kinase inhibitors. Combined, these findings demonstrate the ability to target receptor tyrosine kinases for degradation using the PROTAC technology and outline the advantages of this degradation-based approach.

PROTAC("Proteolysis Targeting Chimera") ist eine schnellw achsende alternative Therapiestrategie,d ie großes Potenzial hat, aktuelle Herausforderungen der Wirkstoffentwicklung zu bewältigen. Die neue Strategie nutzt niedermolekulare Verbindungen, um Zielproteine zur zellulären Ubiquitinierungsmaschinerie und dadurcha nd as Proteasom zu rekrutieren. Hier beschreiben wir die Synthese von PROTACs, die den Abbau von c-ABL und BCR-ABL durchd ie Rekrutierung der Cereblon-oder Von-Hippel-Lindau-E3-Ligasen auslçsen. Die Fähigkeit eines PROTAC, Proteinabbau zu induzieren, beruht nichtallein auf der Wechselwirkung mit dem Zielprotein -die Identität des Liganden, der an das Zielprotein bindet, und der rekrutierten E3-Ligase beeinflusst weitgehend das Abbauprofil des PROTAC. Als Ausgangspunkt für weitere Entwicklungen sollten daher sowohl der Ligand, der an das Zielprotein bindet, als auchd er E3-Ligase-Ligand variiert werden, um auf dem schnellsten Wege inen PROTACm it gewünschtem Abbauprofil zu erstellen.