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e23066 Background: Proteasome as a hub protease of the ubiquitin proteasome pathway is an established anticancer drug target. Several drugs that inhibit proteasome are currently used to successfully treat aggressive blood cancers. These drugs are based on their competition with protein substrates of proteasome. However, efficacy of these drugs toward solid cancers is inadequate. Besides, the side effects and developing drug resistance are increasingly hampering the therapy. Therefore, there is an unmet challenge to develop new types of proteasome targeting compounds that are efficient against solid cancers and utilize other mechanisms to stop proteasome. Here we present a compound with a novel molecular mechanism, potentially bypassing limitations of the available drugs. Methods: We rationally designed and synthesized a series of small molecule “B” compounds, derivatives of a binding domain of seco-rapamycin that noncompetitively interfere with peptidase activities of proteasome. We tested effects of the compounds in vitro on purified proteasome, in cellulo with selected cancer cell lines and in a xenograft mouse model of prostate cancer. Results: We found that compound B1 binds to the catalytic core of proteasome far from the catalytic sites, destabilizes assembly of the 26S proteasome responsible for digest of polyUb substrates and allosterically inhibits its proteolytic activities. Molecularly, B1 impedes the gating mechanism responsible for substrate uptake as found with AFM. Tryptophan fluorescence indicates that B1 changes proteasome fold and the binding mode of competitive inhibitors. B1 substantially decreases viability of selected cancer cell lines and shifts their mechanical phenotype toward noncancerous status. B1 synergizes with bortezomib decreasing the IC50 5-10 fold. In a xenograft hormone resistant prostate cancer model, B1 treatment leads to shrinkage of the tumor size, decreases enumeration of aggressive, EpCAM+ CTCs and shifts the macrophage profile toward predator M1 type. Conclusions: B1 compounds constitute a new class of noncompetitive allosteric inhibitors of proteasome that could be useful to develop to treat aggressive prostate cancers alone or in synergy with competitive inhibitors.

e14113Background: The ubiquitin-proteasome pathway is responsible for the most of regulated intracellular protein degradation in human cells. The proteasome, a major protease of the pathway, is a r...

11045 Background: Advance PCa patients (pts) on androgen-deprivation therapy (ADT) eventually develop castrate-resistance (CR) disease. Men failing to achieve PSA ≤ 4ng/mL after 7 months of ADT hav...