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Beschreibung

A cell-permeable and aqueous soluble (~ 1 mg/mL or 2.26 mM at pH 7.4) biphenylylpentanoic acid that selectively inhibits human, but not yeast, E2 Ub-conjugating enzyme Cdc34- dependent substrates ubiquitinations in p27kip1-SCFSkp2, Sic1-SCFCdc4 (IC50 = 1.72 & 2.5 µ,M, respectively), Cyclin E-SCFFbw7, IkappaBalpha-SCFbetaTrCP ubiquitination assays and induces cellular p27kip1 and cyclin E accumulation (30 µ,M for 16 h in PC-3 cultures), displaying no affinity or inhibitory activity against other E1 (Uba1), E2 (Cdc34B/Ube2R2,Ube2G1, UbeU1), HECT E3 (SMURF 2, UbcH7), or RING E3 (Rnf168) tested. CC0651 is shown to target Ub-bound Cdc34 with a 14-fold higher affinity than the non-Ub-bound Cdc34 via an allosteric binding pocket at the periphery of the Cdc34-Ub interface. In addition to inhibit the reactivity of the Cdc34-Ub complex via direct binding, the CC0651-bound Cdc34-Ub complex itself is reported to exhibit higher affinity toward SCF E3 complex and thereby exhibit a dominant negative effect by effectively competing against functional Cdc34-Ub complex for SCF binding., A cell-permeable biphenylylpentanoic acid compound that acts as a selective allosteric inhibitor of E2 ubiquitin-conjugating enzyme Cdc34 (IC50 = 2.5 µ,M in a Sic1-SCFCdc4 assay) without affecting the activities of E1 or E3 ligases. Reported to act by trapping a weak interaction between ubiquitin and the E2 donor ubiquitin-binding site and may serve as a molecular bridge between Cdc34A and ubiquitin. Binds to Cdc34ACAT alone with an EC50 value of 267 µ,M, but in the presence of ubiquitin, this affinity is significantly increased (EC50 = 19 µ,M). Does not disrupt the interaction of Cdc34A with the RING domain of Rbx1 and is suggested to even moderately stabilize this interaction. Shown to inhibit p27Kip1 ubiquitination (IC50 = 1.72 µ,M) and reduce PC-3 cancer cells proliferation (~30 µ,M).Please note that the molecular weight for this compound is batch-specific due to variable water content.