Peptido Sulfonyl Fluorides as New Powerful Proteasome Inhibitors

Abstract

A new class of potent proteasome inhibitors is described, of which the members contain an amino acid inspired sulfonyl fluoride as the electrophilic trap. In total, 24 peptido sulfonyl fluoride inhibitors have been designed and synthesized, which were inspired by the backbone sequences of the proteasome inhibitors bortezomib, epoxomicin, and Cbz-Leu(3)-aldehyde. Nine of them were very potent proteasome inhibitors, the best of which had an IC(50) of 7 nM. A number of the peptido sulfonyl fluoride inhibitors were found to be highly selective for the β5 proteasome subunit.

The presence of C/EBPα and its degradation are both required for TRIB2-mediated leukaemia

“…6A panel 4 and 5). Second generation irreversible proteasome inhibitors (28,29) also showed selective killing of high TRIB2 (lentiviral Phr-GFP) expressing AML cells as assessed by cell viability (Fig. 6B).…”

Proteasome inhibition by new dual warhead containing peptido vinyl sulfonyl fluorides

“…**hier iets zeggen dat de PSF ook erg goed werkt voor 5c, nu lijkt het dat dit niet zo is*** The sequences of inhibitors 10 and 11 were chosen based on earlier results with our most potent PSF proteasome inhibitors 17 and 18 (IC50-values 89 nM and 18 nM, respectively, Figure 2). [16] Evaluation of the proteasome inhibitory activity gave IC50-values of 218 nM and 99 nM for PVSF compounds 10 and 11, respectively (Figure 1). At first we were somewhat surprised by the diminished activity of the PVSF's as compared to PSF's 17 and 18, respectively.…”

“…Although a PVSF may be more reactive than a PSF, the sulfonyl fluoride warhead part may occupy a less favourable P1' position because it is further positioned from the P1 side chain, leading a reduced inhibition. Therefore, we believe that by evaluating different amino acid sequences with the vinyl sulfonyl fluoride dual warhead, as was done with the sulfonyl fluoride warhead, [16] even lower IC50-values may be obtained. To investigate whether the proposed formation within the enzyme of a 7-membered ring adduct could be observed by chemo-synthesis, in parallel, the reactivity of a simplified peptido vinylsulfonyl fluoride (8) was studied with H-ThrVal-N(H)Me (13) as a model of the threonine residue present in the catalytic site of the proteasome (Scheme 4).…”

Selektive Inhibition des Immunoproteasoms durch ligandeninduzierte Vernetzung des katalytischen Zentrums

“…[5,12,13] Allerdings legen Studien über verschiedene Kopfgruppen sowie peptidische Sulfonylfluorid-Proteasom-Inhibitoren (PSF) nahe, dass auch funktionelle Gruppen einen direkten Einfluss auf die Selektivität für aktive b-Untereinheiten nehmen. [14][15][16] Bemerkenswerterweise hemmen PSF-Verbindungen die CP-Aktivität im nanomolaren Bereich. [16] Dabei stellen sie bisher die einzigen peptidischen CP-Inhibitoren dar, deren elektrophile Kopfgruppe um eine Methylen-Einheit versetzt ist, was einen außergewçhnlichen Reaktionsmechanismus erfordert.…”