Optimization of Subsite Binding to the β5 Subunit of the Human 20S Proteasome Using Vinyl Sulfones and 2-Keto-1,3,4-oxadiazoles:  Syntheses and Cellular Properties of Potent, Selective Proteasome Inhibitors

Rydzewski, Robert M.; Burrill, Leland C.; Mendonca, Rohan; Palmer, James T.; Rice, Mark J.; Tahilramani, R.; Bass, Kathryn E.; Leung, Ling; Gjerstad, Erik; Janc, James W.; Lin, Pei

doi:10.1021/jm058289o

Cited by 40 publications

(39 citation statements)

References 43 publications

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“…Although the calculated model did not show any interaction between the substituent at P2 position and residues of proteasome, the authors found that a bulky group at this position would prevent water molecules from attacking the covalent inhibitor and thus it would stabilize the complex and improve the activity. This theoretical result was consistent with the results of a series of peptide-like vinyl sulfones [80].…”

Section: Covalent Dockingsupporting

confidence: 91%

Progress of Computer-Aided Drug Design (CADD) of Proteasome Inhibitors

Li¹,

Liu

Zhu³

et al. 2011

CTMC

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The target proteasome has been the focus of drug discovery since the first drug bortezomib was launched in 2003. Many structurally diverse proteasome inhibitors were discovered and even some of them entered the clinical trials. Due to rapid technological progress in chemistry, bioinformatics, structural biology and computer technology, computer-aided drug design (CADD) plays a more and more important role in today's drug discovery. Many CADD technologies were employed in designing various inhibitors of proteasome in the past years. This review gives a global description of the development of computer-aided proteasome inhibitor design by using different commercial or academic software. The binding modes of some structurally novel inhibitors with proteasome were visualized with these new technologies.

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Section: Covalent Dockingsupporting

confidence: 91%

Progress of Computer-Aided Drug Design (CADD) of Proteasome Inhibitors

Li¹,

Liu

Zhu³

et al. 2011

CTMC

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“…Monosubstituted oxadiazoles are deprotonated at the ring carbon atom to give the corresponding anion, which has been subsequently alkylated with various alkylating agents. Thus, for example, 2-substituted-1,3,4-oxadiazoles 959 after treatment with butyllithium in the presence of MgBr 2 diethyl etherate in THF, [613,614].…”

Section: Reactions Of Substituentsmentioning

confidence: 99%

Oxadiazoles

Romeo¹,

Chiacchio²

2011

Modern Heterocyclic Chemistry

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“…Various natural and synthetic compounds that contain electrophilic centres or ‘warheads’ inhibit the proteasome by forming covalent adducts with these active-site threonine residues, including peptide aldehydes, vinyl sulfones, boronic acids, α′β′-epoxyketones, 2-keto-1,3,4-oxadiazoles and β-lactones (Figure 1A) [4–6,9–11]. The di-peptide boronic acid bortezomib (PS-341 or VELCADE®, Millennium Pharmaceuticals, Inc.) is among the most potent, stable and selective of these inhibitors [12–15], and shows nanomolar potency with respect to cytotoxicity across a broad range of human tumour cell types in vitro [13,14].…”

Section: Introductionmentioning

confidence: 99%

Characterization of a new series of non-covalent proteasome inhibitors with exquisite potency and selectivity for the 20S β5-subunit

Blackburn

Gigstad

Hales

et al. 2010

Biochemical Journal

137

155

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The mammalian 26S proteasome is a 2500 kDa multi-catalytic complex involved in intracellular protein degradation. We describe the synthesis and properties of a novel series of non-covalent di-peptide inhibitors of the proteasome used on a capped tri-peptide that was first identified by high-throughput screening of a library of approx. 350000 compounds for inhibitors of the ubiquitin–proteasome system in cells. We show that these compounds are entirely selective for the β5 (chymotrypsin-like) site over the β1 (caspase-like) and β2 (trypsin-like) sites of the 20S core particle of the proteasome, and over a panel of less closely related proteases. Compound optimization, guided by X-ray crystallography of the liganded 20S core particle, confirmed their non-covalent binding mode and provided a structural basis for their enhanced in vitro and cellular potencies. We demonstrate that such compounds show low nanomolar IC50 values for the human 20S β5 site in vitro, and that pharmacological inhibition of this site in cells is sufficient to potently inhibit the degradation of a tetra-ubiquitin–luciferase reporter, activation of NFκB (nuclear factor κB) in response to TNF-α (tumour necrosis factor-α) and the proliferation of cancer cells. Finally, we identified capped di-peptides that show differential selectivity for the β5 site of the constitutively expressed proteasome and immunoproteasome in vitro and in B-cell lymphomas. Collectively, these studies describe the synthesis, activity and binding mode of a new series of non-covalent proteasome inhibitors with unprecedented potency and selectivity for the β5 site, and which can discriminate between the constitutive proteasome and immunoproteasome in vitro and in cells.

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Optimization of Subsite Binding to the β5 Subunit of the Human 20S Proteasome Using Vinyl Sulfones and 2-Keto-1,3,4-oxadiazoles: Syntheses and Cellular Properties of Potent, Selective Proteasome Inhibitors

Cited by 40 publications

References 43 publications

Progress of Computer-Aided Drug Design (CADD) of Proteasome Inhibitors

Progress of Computer-Aided Drug Design (CADD) of Proteasome Inhibitors

Oxadiazoles

Characterization of a new series of non-covalent proteasome inhibitors with exquisite potency and selectivity for the 20S β5-subunit

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