Modulares PROTAC‐Design zum Abbau von onkogenem BCR‐ABL

Abstract

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.

Bifunctional Small‐Molecule Ligands of K‐Ras Induce Its Association with Immunophilin Proteins

“…A plausible explanation is that long linear linkers impart more conformational flexibility and incur higher entropic cost upon compound binding. Though we have not established extensive structure-activity relationship, the trend we observed here is congruent with previous reports on bifunctional compounds designed for targeted protein degradation [24] .…”

Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta

“…Over the past decade, PROTACs have been developed to address an ever-expanding collection of target proteins. Owing to the availability of well-validated chemical matter to repurpose as PROTAC warheads, the majority of early reports focused on degraders of hormone receptors [10][11][12][13], BET-family proteins [14][15][16] and kinases [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. More recently, the applicability of PROTACs has been broadened to include multi-functional proteins (e.g., TRIM24 [34], SMARCA2 [35] tau [36,37]), and HaloTag7-fused proteins for chemical genetics [38].…”

“…A key challenge in this rapidly-growing field, however, remains unresolved: how to design effective PROTACs in a rational manner. A important early paper in this field advocated for rapidly varying both the target-engaging warhead and the E3-recruiting moiety in search of a useful starting point [17], and this strategy is still used today. This approach can only hope to capture only a fraction of the candidate PROTACs one might envision for degrading a given target, however, because the linker used to join these groups also plays a critical role in efficacy.…”

Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure–Degradation Relationships

“…[16,17] Indeed, IMiDs have been widely used as E3 recruiting elements to enable the degradation of aw ide variety of targets. [18][19][20][21][22][23][24][25] Intrigued by the "molecular glue" mechanism of these compounds, we sought to explore the structure-degradation relationships (SDR) of IMiD analogues with an aim to elucidate the requirements for neo-substrater ecruitmenta nd the development of high-affinity recruiting elementsf or use in PROTACs. Previous SAR studies have provenc hallengingd ue to both time-consuming synthesis and insufficient knowledge surrounding the mechanism of action prior to 2014.…”