Discovery of a non-covalent ligand for Rpn-13, a therapeutic target for hematological cancers.

Autor: Loy CA; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 West Stadium Avenue, West Lafayette, IN 47907, United States., Muli CS; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 West Stadium Avenue, West Lafayette, IN 47907, United States., Ali EMH; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 West Stadium Avenue, West Lafayette, IN 47907, United States., Xie D; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 West Stadium Avenue, West Lafayette, IN 47907, United States., Ahmed MH; Atomwise Inc., San Francisco, CA, United States., Beth Post C; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 West Stadium Avenue, West Lafayette, IN 47907, United States., Trader DJ; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 West Stadium Avenue, West Lafayette, IN 47907, United States. Electronic address: dtrader@purdue.edu.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2023 Oct 15; Vol. 95, pp. 129485. Date of Electronic Publication: 2023 Sep 14.
DOI: 10.1016/j.bmcl.2023.129485
Abstrakt: The ubiquitin-proteasome system serves as the major proteolytic degradation pathway in eukaryotic cells. Many inhibitors that covalently bind to the proteasome's active sites have been developed for hematological cancers, but resistance can arise in patients. To overcome limitations of active-site proteasome inhibitors, we and others have focused on developing ligands that target subunits on the 19S regulatory particle (19S RP). One such 19S RP subunit, Rpn-13, is a ubiquitin receptor required for hematological cancers to rapidly degrade proteins to avoid apoptosis. Reported Rpn-13 inhibitors covalently bind to the Rpn-13's Pru domain and have been effective anti-hematological cancer agents. Here, we describe the discovery of TCL-1, a non-covalent binder to the Pru domain. Optimization of TCL-1's carboxylate group to an ester increases its cytotoxicity in hematological cancer cell lines. Altogether, our data provides a new scaffold for future medicinal chemistry optimization to target Rpn-13 therapeutically.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prof. Trader is a shareholder and consultant for Booster Therapeutics, GmbH. Other authors declares no conflict of interest.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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