Identification of chemical scaffolds for targeting ubiquitin-specific protease 11 (USP11) through high-throughput virtual screening
Lee, Hobin ; Hurh, Sunghoon ; Kang, Soomin ; Yoon, Jihwan ; Hwang, Jong-Ik ; Logan, Derek T. LU
and Kim, Hong-Rae
(2025)
In Journal of Enzyme Inhibition and Medicinal Chemistry
40(1).
- Abstract
USP11 is a promising therapeutic target implicated in Alzheimer’s disease and various cancers; however, no specific inhibitors are currently available, with the only known inhibitor being mitoxantrone, which primarily targets topoisomerase II. To identify novel chemical starting points, we conducted high-throughput virtual screening using a USP11 homology model. Screening over 600,000 compounds yielded five structurally distinct hits with significant inhibitory activity. Biochemical validation highlighted two promising scaffolds: benzoxadiazole derivatives and pyrrolo-phenylamidine analogues, both demonstrating structure-dependent inhibition and tractable SAR profiles. Docking studies further characterised their binding modes,... (More)
USP11 is a promising therapeutic target implicated in Alzheimer’s disease and various cancers; however, no specific inhibitors are currently available, with the only known inhibitor being mitoxantrone, which primarily targets topoisomerase II. To identify novel chemical starting points, we conducted high-throughput virtual screening using a USP11 homology model. Screening over 600,000 compounds yielded five structurally distinct hits with significant inhibitory activity. Biochemical validation highlighted two promising scaffolds: benzoxadiazole derivatives and pyrrolo-phenylamidine analogues, both demonstrating structure-dependent inhibition and tractable SAR profiles. Docking studies further characterised their binding modes, supporting their potential for optimisation. Hydroxyphenyl hydrazone analogues raised PAINS-related concerns, while compounds such as squalamine were deprioritized due to weak binding affinity and structural complexity. Overall, this study provides valuable scaffolds and mechanistic insights that can inform future development of potent, selective USP11 inhibitors.
(Less)
- author
- Lee, Hobin
; Hurh, Sunghoon
; Kang, Soomin
; Yoon, Jihwan
; Hwang, Jong-Ik
; Logan, Derek T.
LU
and Kim, Hong-Rae
- organization
- publishing date
- 2025
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- inhibitor, protein-ligand interactions, Ubiquitin-specific protease, virtual screening
- in
- Journal of Enzyme Inhibition and Medicinal Chemistry
- volume
- 40
- issue
- 1
- article number
- 2518191
- pages
- 11 pages
- publisher
- Informa Healthcare
- external identifiers
-
- scopus:105009525478
- pmid:40588719
- ISSN
- 1475-6366
- DOI
- 10.1080/14756366.2025.2518191
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © 2025 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
- id
- 42b71cb7-5012-4c11-9952-28902190b667
- date added to LUP
- 2025-11-10 09:11:00
- date last changed
- 2025-11-13 12:43:32
@article{42b71cb7-5012-4c11-9952-28902190b667,
abstract = {{<p>USP11 is a promising therapeutic target implicated in Alzheimer’s disease and various cancers; however, no specific inhibitors are currently available, with the only known inhibitor being mitoxantrone, which primarily targets topoisomerase II. To identify novel chemical starting points, we conducted high-throughput virtual screening using a USP11 homology model. Screening over 600,000 compounds yielded five structurally distinct hits with significant inhibitory activity. Biochemical validation highlighted two promising scaffolds: benzoxadiazole derivatives and pyrrolo-phenylamidine analogues, both demonstrating structure-dependent inhibition and tractable SAR profiles. Docking studies further characterised their binding modes, supporting their potential for optimisation. Hydroxyphenyl hydrazone analogues raised PAINS-related concerns, while compounds such as squalamine were deprioritized due to weak binding affinity and structural complexity. Overall, this study provides valuable scaffolds and mechanistic insights that can inform future development of potent, selective USP11 inhibitors.</p>}},
author = {{Lee, Hobin and Hurh, Sunghoon and Kang, Soomin and Yoon, Jihwan and Hwang, Jong-Ik and Logan, Derek T. and Kim, Hong-Rae}},
issn = {{1475-6366}},
keywords = {{inhibitor; protein-ligand interactions; Ubiquitin-specific protease; virtual screening}},
language = {{eng}},
number = {{1}},
publisher = {{Informa Healthcare}},
series = {{Journal of Enzyme Inhibition and Medicinal Chemistry}},
title = {{Identification of chemical scaffolds for targeting ubiquitin-specific protease 11 (USP11) through high-throughput virtual screening}},
url = {{http://dx.doi.org/10.1080/14756366.2025.2518191}},
doi = {{10.1080/14756366.2025.2518191}},
volume = {{40}},
year = {{2025}},
}