Discovery and Characterization of BAY-805, a Potent and Selective Inhibitor of Ubiquitin-Specific Protease USP21

Göricke, Fabian; Vu, Victoria; Smith, Leanna; Scheib, U.; Böhm, Raphael; Akkiliç, Namık; Wohlfahrt, Gerd; Weiske, Jörg; Bömer, Ulf; Brzezinka, Krzysztof; Lindner, Niels; Lienau, Philip; Gradl, Stefan; Beck, Hartmut; Brown, Peter J.; Santhakumar, V.; Vedadi, Masoud; Baršytė-Lovejoy, Dalia; Arrowsmith, C.H.; Schmees, Norbert; Petersen, Kirstin

doi:10.1021/acs.jmedchem.2c01933

Cited by 11 publications

(4 citation statements)

References 54 publications

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“…One study showed that gallic acid causes PD-L1 downregulation by inhibiting USP21-mediated deubiquitination. BAY-805 is another potent and selective USP21 inhibitor[ 94 , 95 ].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of the role of ubiquitin-specific peptidases in colorectal cancer: A systematic review

Al-Balushi,

Al Marzouqi,

Tavoosi

et al. 2024

World J Gastrointest Oncol

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BACKGROUND Colorectal cancer (CRC) is the third most frequent and the second most fatal cancer. The search for more effective drugs to treat this disease is ongoing. A better understanding of the mechanisms of CRC development and progression may reveal new therapeutic strategies. Ubiquitin-specific peptidases (USPs), the largest group of the deubiquitinase protein family, have long been implicated in various cancers. There have been numerous studies on the role of USPs in CRC; however, a comprehensive view of this role is lacking. AIM To provide a systematic review of the studies investigating the roles and functions of USPs in CRC. METHODS We systematically queried the MEDLINE (via PubMed), Scopus, and Web of Science databases. RESULTS Our study highlights the pivotal role of various USPs in several processes implicated in CRC: Regulation of the cell cycle, apoptosis, cancer stemness, epithelial–mesenchymal transition, metastasis, DNA repair, and drug resistance. The findings of this study suggest that USPs have great potential as drug targets and noninvasive biomarkers in CRC. The dysregulation of USPs in CRC contributes to drug resistance through multiple mechanisms. CONCLUSION Targeting specific USPs involved in drug resistance pathways could provide a novel therapeutic strategy for overcoming resistance to current treatment regimens in CRC.

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“…One study showed that gallic acid causes PD-L1 downregulation by inhibiting USP21-mediated deubiquitination. BAY-805 is another potent and selective USP21 inhibitor[ 94 , 95 ].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of the role of ubiquitin-specific peptidases in colorectal cancer: A systematic review

Al-Balushi,

Al Marzouqi,

Tavoosi

et al. 2024

World J Gastrointest Oncol

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“…Bayer's first co-developed chemical probe was the SMYD2 inhibitor BAY-598 for cancer. 43 The latest example is the USP21 inhibitor BAY-805 44 which is the first potent and selective probe for USP21. It will help researchers gain new insights into the intriguing disease biology of immune-oncology.…”

Section: Summaries Of Private Sector Contributions To Target 2035mentioning

confidence: 99%

Target 2035 – an update on private sector contributions

Ackloo

Antolín

Bartolomé³

et al. 2023

RSC Med. Chem.

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“…The UPS2 protein has been labeled a "master regulator of apoptosis" since USP2 can remove ubiquitin chains from RIP1 and TRAF2, regulate TNF-TNFR1-mediated cell death, and upregulate the transcription of IkBα [91]. Like USP2, USP21 was also reported to deubiquitinate RIP1 [92] and the selective USP21 inhibitor compound BAY-805 may have therapeutic potential in cancer [93]. Both CYLD and TNFAIP3 have been shown to also contribute to the regulation of NF-κB [79,81].…”

Section: Dubs In Ependymomamentioning

confidence: 99%

DUBing Primary Tumors of the Central Nervous System: Regulatory Roles of Deubiquitinases

Klonisch,

Logue,

Hombach-Klonisch

et al. 2023

Biomolecules

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The ubiquitin proteasome system (UPS) utilizes an orchestrated enzymatic cascade of E1, E2, and E3 ligases to add single or multiple ubiquitin-like molecules as post-translational modification (PTM) to proteins. Ubiquitination can alter protein functions and/or mark ubiquitinated proteins for proteasomal degradation but deubiquitinases (DUBs) can reverse protein ubiquitination. While the importance of DUBs as regulatory factors in the UPS is undisputed, many questions remain on DUB selectivity for protein targeting, their mechanism of action, and the impact of DUBs on the regulation of diverse biological processes. Furthermore, little is known about the expression and role of DUBs in tumors of the human central nervous system (CNS). In this comprehensive review, we have used publicly available transcriptional datasets to determine the gene expression profiles of 99 deubiquitinases (DUBs) from five major DUB families in seven primary pediatric and adult CNS tumor entities. Our analysis identified selected DUBs as potential new functional players and biomarkers with prognostic value in specific subtypes of primary CNS tumors. Collectively, our analysis highlights an emerging role for DUBs in regulating CNS tumor cell biology and offers a rationale for future therapeutic targeting of DUBs in CNS tumors.

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Discovery and Characterization of BAY-805, a Potent and Selective Inhibitor of Ubiquitin-Specific Protease USP21

Cited by 11 publications

References 54 publications

Comprehensive analysis of the role of ubiquitin-specific peptidases in colorectal cancer: A systematic review

Comprehensive analysis of the role of ubiquitin-specific peptidases in colorectal cancer: A systematic review

Target 2035 – an update on private sector contributions

DUBing Primary Tumors of the Central Nervous System: Regulatory Roles of Deubiquitinases

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