Discovery of a potent and highly β1 specific proteasome inhibitor from a focused library of urea-containing peptide vinyl sulfones and peptide epoxyketones

Linden, Wouter A. van der; Willems, Lianne I.; Shabaneh, Tamer B.; Li, Nan; Ruben, Mark; Florea, Bogdan I.; Marel, Gijs A. van der; Kaiser, Markus; Kisselev, Alexei F.; Overkleeft, Herman S.

doi:10.1039/c1ob06554h

Cited by 29 publications

(27 citation statements)

References 43 publications

(134 reference statements)

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“…The success of these small molecules has generated substantial interest in developing inhibitors that target other key elements of the proteasome. 5-9 …”

Section: Introductionmentioning

confidence: 99%

Discovery of an Inhibitor of the Proteasome Subunit Rpn11

Perez

Li²,

Parlati³

et al. 2017

J. Med. Chem.

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The proteasome plays a crucial role in degradation of normal proteins that happen to be constitutively or inducibly unstable, and in this capacity it plays a regulatory role. Additionally, it degrades abnormal/damaged/mutant/misfolded proteins, which serves a quality-control function. Inhibitors of the proteasome have been validated in the treatment of multiple myeloma, with several FDA-approved therapeutics. Rpn11 is a Zn2+-dependent metalloisopeptidase that hydrolyzes ubiquitin from tagged proteins that are trafficked to the proteasome for degradation. A fragment-based drug discovery (FBDD) approach was utilized to identify fragments with activity against Rpn11. Screening of a library of metal-binding pharmacophores (MBPs) revealed that 8-thioquinoline (8TQ, IC50 value ~2.5 μM) displayed strong inhibition of Rpn11. Further synthetic elaboration of 8TQ yielded a small molecule compound (35, IC50 value ~300 nM) that is a potent and selective inhibitor of Rpn11 that blocks proliferation of tumor cells in culture.

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“…The success of these small molecules has generated substantial interest in developing inhibitors that target other key elements of the proteasome. 5-9 …”

Section: Introductionmentioning

confidence: 99%

Discovery of an Inhibitor of the Proteasome Subunit Rpn11

Perez

Li²,

Parlati³

et al. 2017

J. Med. Chem.

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“…YU-102 (Myung et al, 2001), NC-001 (Britton et al, 2009), and LU-001 (van der Linden et al, 2012) inhibit β1 and β1i sites.…”

Section: Figurementioning

confidence: 99%

Proteasome Inhibitors: An Expanding Army Attacking a Unique Target

Kisselev

Linden

Overkleeft

2012

Chemistry & Biology

480

482

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Proteasomes are large, multisubunit proteolytic complexes presenting multiple targets for therapeutic intervention. The 26S proteasome consists of a 20S proteolytic core and one or two 19S regulatory particles. The 20S core contains three types of active sites. Many structurally diverse inhibitors of these active sites, both natural product and synthetic, have been discovered in the last two decades. One, bortezomib, is used clinically for treatment of multiple myeloma, mantle cell lymphoma, and acute allograft rejection. Five more recently developed proteasome inhibitors are in trials for treatment of myeloma and other cancers. Proteasome inhibitors also have activity in animal models of autoimmune and inflammatory diseases, reperfusion injury, promote bone and hair growth, and can potentially be used as anti-infectives. In addition, inhibitors of ATPases and deubiquitinases of 19S regulatory particles have been discovered in the last decade.

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“…Hydrolyzation by the 20S proteasome was significantly slower for charged or polar residues. Since the proteasome structure has three pairs of catalytically active subunits with distinct specificities (chymotrypsin, trypsin, and caspase), we repeated these experiments in the presence of a trypsin subunit inhibitor (PR671A) [20]. In effect, a 96% reduction in activity was recorded.…”

Section: Resultsmentioning

confidence: 99%

A Peptidomimetic Fluorescent Probe to Detect the Trypsin β2 Subunit of the Human 20S Proteasome

Wysocka

Romanowska

Gruba

et al. 2020

IJMS

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This work describes the chemical synthesis, combinatorial selection, and enzymatic evaluation of peptidomimetic fluorescent substrates specific for the trypsin-like (β2) subunit of the 20S human proteasome. After deconvolution of a library comprising nearly 6000 compounds composed of peg substituted diaminopropionic acid DAPEG building blocks, the sequence ABZ–Dap(O2(Cbz))–Dap(GO1)–Dap(O2(Cbz))–Arg–ANB–NH2, where ABZ is 2-aminobenzoic acid, and ANB- 5 amino 2- nitro benzoic acid was selected. Its cleavage followed sigmoidal kinetics, characteristic for allosteric enzymes, with Km = 3.22 ± 0.02 μM, kcat = 245 s−1, and kcat/Km = 7.61 × 107 M−1 s−1. This process was practically halted when a selective inhibitor of the β2 subunit of the 20S human proteasome was supplemented to the reaction system. Titration of the substrate resulting in decreased amounts of proteasome 20S produced a linear signal up to 10−11 M. Using this substrate, we detected human proteasome 20S in human urine samples taken from the bladders of cancer patients. This observation could be useful for the noninvasive diagnosis of this severe disease.

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Discovery of a potent and highly β1 specific proteasome inhibitor from a focused library of urea-containing peptide vinyl sulfones and peptide epoxyketones

Cited by 29 publications

References 43 publications

Discovery of an Inhibitor of the Proteasome Subunit Rpn11

Discovery of an Inhibitor of the Proteasome Subunit Rpn11

Proteasome Inhibitors: An Expanding Army Attacking a Unique Target

A Peptidomimetic Fluorescent Probe to Detect the Trypsin β2 Subunit of the Human 20S Proteasome

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