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PROTAC („Proteolysis Targeting Chimera”) ist eine schnell wachsende alternative Therapiestrategie, die großes Potenzial hat, aktuelle Herausforderungen der Wirkstoffentwicklung zu bew.ltigen. Die neue Strategie nutzt niedermolekulare Verbindungen, um Zielproteine zur zellul.ren Ubiquitinierungsmaschinerie und dadurch an das Proteasom zu rekrutieren. Hier beschreiben wir die Synthese von PROTACs, die den Abbau von c-ABL und BCR-ABL durch die Rekrutierung der Cereblon- oder Von-Hippel-Lindau-E3-Ligasen auslösen. Die F.higkeit eines PROTAC, Proteinabbau zu induzieren, beruht nicht allein auf der Wechselwirkung mit dem Zielprotein - die Identit.t 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 auch der E3-Ligase-Ligand variiert werden, um auf dem schnellsten Weg einen PROTAC mit gew ünschtem Abbauprofil zu erstellen. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A straightforward synthesis of air- and water-stable bis-cationic macrocyclic imidazolylboronium anion receptors is described herein. By taking advantage of the bulky and rigid 9-borabicyclo[3.3.1]-nonane (9-BBN) attaching point and a well-designed bis-imidazolylaryl, highly stable dimeric imidazolylboronium macrocycles were synthesized. Additionally, NMR spectroscopy ((1) H, DOSY, and HOESY), mass spectrometry (MS), and X-ray diffraction studies revealed that these macrocyclic scaffolds can bind several monoanions with high association constants in DMSO, and are particularly sensitive for the MS detection of anions (with concentrations in the nm range). This anion/receptor interaction involves eight C-H binding sites, which include Csp2 -H and unusual Csp3 -H hydrogen-bonding donors., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The current inhibitor-based approach to therapeutics has inherent limitations owing to its occupancy-based model: 1) there is a need to maintain high systemic exposure to ensure sufficient in vivo inhibition, 2) high in vivo concentrations bring potential for off-target side effects, and 3) there is a need to bind to an active site, thus limiting the drug target space. As an alternative, induced protein degradation lacks these limitations. Based on an event-driven model, this approach offers a novel catalytic mechanism to irreversibly inhibit protein function by targeting protein destruction through recruitment to the cellular quality control machinery. Prior protein degrading strategies have lacked therapeutic potential. However, recent reports of small-molecule-based proteolysis-targeting chimeras (PROTACs) have demonstrated that this technology can effectively decrease the cellular levels of several protein classes., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)