ArticleACS chemical biology2013
Noncompetitive modulation of the proteasome by imidazoline scaffolds overcomes bortezomib resistance and delays MM tumor growth in vivo.
Article in ACS chemical biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 32 citations in OpenAlex.
- Small Molecule 20S Proteasome Enhancer Regulates MYC Protein Stability and Exhibits Antitumor Activity in Multiple Myeloma.Biomedicines · 2022Article
- Dihydroquinazolines enhance 20S proteasome activity and induce degradation of α-synuclein, an intrinsically disordered protein associated with neurodegeneration.Bioorganic & medicinal chemistry letters · 2021Article
- Regulation of Autophagic Flux by the 20S Proteasome.Cell chemical biology · 2019Article
- Proline- and Arginine-Rich Peptides as Flexible Allosteric Modulators of Human Proteasome Activity.Journal of medicinal chemistry · 2019Article
- Small Molecule Modulation of Proteasome Assembly.Biochemistry · 2018Article
- Structure of human immunoproteasome with a reversible and noncompetitive inhibitor that selectively inhibits activated lymphocytes.Nature communications · 2017Article
- Analysing the effect of IInflammopharmacology · 2017Article
- Substituted quinolines as noncovalent proteasome inhibitors.Bioorganic & medicinal chemistry · 2016Article
- Review
- Proteasome inhibitors with pyrazole scaffolds from structure-based virtual screening.Journal of medicinal chemistry · 2015Article
- Article
- Small-molecule control of intracellular protein levels through modulation of the ubiquitin proteasome system.Angewandte Chemie (International ed. in English) · 2014Review
- Inhibition of the human proteasome by imidazoline scaffolds.Journal of medicinal chemistry · 2013Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Multiple myeloma (MM) is a malignant disorder of differentiated B-cells for which standard care involves the inhibition of the proteasome. All clinically used proteasome inhibitors, including the chemotherapeutic drug bortezomib, target the catalytic active sites of the proteasome and inhibit protein proteolysis by competing with substrate binding. However, nearly all (~97%) patients become intolerant or resistant to treatments within a few years, after which the average survival time is less than 1 year. We describe herein the inhibition of the human proteasome via a noncompetitive mechanism by the imidazoline scaffold, TCH-13. Consistent with a mechanism distinct from that of competitive inhibitors, TCH-013 acts additively with and overcomes resistance to bortezomib. Importantly, TCH-013 induces apoptosis in a panel of myeloma and leukemia cell lines, but in contrast, normal lymphocytes, primary bone marrow stromal cells (hBMSC), and macrophages are resistant to its cytotoxic effects. TCH-013 was equally effective in blocking MM cell growth in co-cultures of MM cells with hBMSC isolated from CD138 negative bone marrow (BM) samples of MM patients. The cellular activity translated well in vivo where TCH-013 delayed tumor growth in an MM xenograft model to a similar extent as bortezomib.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.