Structure-Based Optimization and Discovery of M3258, a Specific Inhibitor of the Immunoproteasome Subunit LMP7 (β5i)
| العنوان: | Structure-Based Optimization and Discovery of M3258, a Specific Inhibitor of the Immunoproteasome Subunit LMP7 (β5i) |
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| المؤلفون: | Felix Rohdich, Stefano Crosignani, Michael Busch, Christina Esdar, Manja Friese-Hamim, Markus Klein, Thomas Fuchss, Oliver Schadt, Djordje Musil, Ugo Zanelli, Michael P. Sanderson, Gina Walter-Bausch, Philip Hewitt, Jeyaprakashnarayanan Seenisamy |
| المصدر: | Journal of Medicinal Chemistry. 64:10230-10245 |
| بيانات النشر: | American Chemical Society (ACS), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Gene isoform, Proteasome Endopeptidase Complex, Dose-Response Relationship, Drug, Molecular Structure, Chemistry, Protein subunit, Protein degradation, medicine.disease, Protein Subunits, Structure-Activity Relationship, Haematopoiesis, Proteasome, Biochemistry, Drug Discovery, medicine, Humans, Molecular Medicine, Potency, Structure based, Proteasome Inhibitors, Multiple myeloma |
| الوصف: | Proteasomes are broadly expressed key components of the ubiquitin-dependent protein degradation pathway containing catalytically active subunits (β1, β2, and β5). LMP7 (β5i) is a subunit of the immunoproteasome, an inducible isoform that is predominantly expressed in hematopoietic cells. Clinically effective pan-proteasome inhibitors for the treatment of multiple myeloma (MM) nonselectively target LMP7 and other subunits of the constitutive proteasome and immunoproteasome with comparable potency, which can limit the therapeutic applicability of these drugs. Here, we describe the discovery and structure-based hit optimization of novel amido boronic acids, which selectively inhibit LMP7 while sparing all other subunits. The exploitation of structural differences between the proteasome subunits culminated in the identification of the highly potent, exquisitely selective, and orally available LMP7 inhibitor 50 (M3258). Based on the strong antitumor activity observed with M3258 in MM models and a favorable preclinical data package, a phase I clinical trial was initiated in relapsed/refractory MM patients. |
| تدمد: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.1c00604 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c1a3d051fc60306aef1b64a7ba1b3e7b https://doi.org/10.1021/acs.jmedchem.1c00604 |
| Rights: | CLOSED |
| رقم الانضمام: | edsair.doi.dedup.....c1a3d051fc60306aef1b64a7ba1b3e7b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15204804 00222623 |
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| DOI: | 10.1021/acs.jmedchem.1c00604 |