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.

The androgen receptor is a major driver of prostate cancer and inhibition of its transcriptional activity using competitive antagonists, such as enzalutamide remains a frontline therapy for prostate cancer management. However, the majority of patients eventually develop drug resistance. We propose that targeting the androgen receptor for degradation via Proteolysis Targeting Chimeras (PROTACs) will be a better therapeutic strategy for targeting androgen receptor signaling in prostate cancer cells. Here we perform a head-to-head comparison between a currently approved androgen receptor antagonist enzalutamide, and its PROTAC derivative, ARCC-4, across different cellular models of prostate cancer drug resistance. ARCC-4 is a low-nanomolar androgen receptor degrader able to degrade about 95% of cellular androgen receptors. ARCC-4 inhibits prostate tumor cell proliferation, degrades clinically relevant androgen receptor point mutants and unlike enzalutamide, retains antiproliferative effect in a high androgen environment. Thus, ARCC-4 exemplifies how protein degradation can address the drug resistance hurdles of enzalutamide.

Targeted therapies for cancer are typically small molecules or monoclonal antibodies that act by inhibiting the activity of specific proteins that drive tumor growth. Although many of these drugs are effective in cancer patients, the response is often not durable because tumor cells develop resistance to the drugs. Another limitation of this strategy is that not all oncogenic driver proteins are "druggable" enzymes or receptors with activities that can be inhibited. Here we describe an alternative approach to targeted therapy that is based on co-opting the cellular quality-control machinery-the ubiquitin-proteasome system-to remove specific cancer-causing proteins from the cell. We first discuss examples of existing cancer drugs that work by degrading specific proteins and then review recent progress in the rational design and preclinical testing of small molecules that induce selective degradation of specific target proteins.

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.