Covalent fragment screening and optimization identifies the chloroacetohydrazide scaffold as inhibitors for ubiquitin C-terminal hydrolase L1
Dysregulation of the ubiquitin-proteasome systems is a hallmark of various disease states including neurodegenerative diseases and cancer. Ubiquitin C-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme, is expressed primarily in the central nervous system under normal physiological conditions,...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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American Chemical Society
2024
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| _version_ | 1826312892785360896 |
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| author | Imhoff, RD Patel, R Safdar, MH Jones, HBL Pinto-Fernandez, A Vendrell, I Chen, H Muli, CS Krabill, AD Kessler, BM Wendt, MK Das, C Flaherty, DP |
| author_facet | Imhoff, RD Patel, R Safdar, MH Jones, HBL Pinto-Fernandez, A Vendrell, I Chen, H Muli, CS Krabill, AD Kessler, BM Wendt, MK Das, C Flaherty, DP |
| author_sort | Imhoff, RD |
| collection | OXFORD |
| description | Dysregulation of the ubiquitin-proteasome systems is a hallmark of various disease states including neurodegenerative diseases and cancer. Ubiquitin C-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme, is expressed primarily in the central nervous system under normal physiological conditions, however, is considered an oncogene in various cancers, including melanoma, lung, breast, and lymphoma. Thus, UCHL1 inhibitors could serve as a viable treatment strategy against these aggressive cancers. Herein, we describe a covalent fragment screen that identified the chloroacetohydrazide scaffold as a covalent UCHL1 inhibitor. Subsequent optimization provided an improved fragment with single-digit micromolar potency against UCHL1 and selectivity over the closely related UCHL3. The molecule demonstrated efficacy in cellular assays of metastasis. Additionally, we report a ligand-bound crystal structure of the most potent molecule in complex with UCHL1, providing insight into the binding mode and information for future optimization. |
| first_indexed | 2024-04-09T03:57:04Z |
| format | Journal article |
| id | oxford-uuid:bb5c605f-e75f-4df2-ba2d-4691bc1a1e32 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:04:00Z |
| publishDate | 2024 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | oxford-uuid:bb5c605f-e75f-4df2-ba2d-4691bc1a1e322024-05-08T16:02:37ZCovalent fragment screening and optimization identifies the chloroacetohydrazide scaffold as inhibitors for ubiquitin C-terminal hydrolase L1Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:bb5c605f-e75f-4df2-ba2d-4691bc1a1e32EnglishSymplectic ElementsAmerican Chemical Society2024Imhoff, RDPatel, RSafdar, MHJones, HBLPinto-Fernandez, AVendrell, IChen, HMuli, CSKrabill, ADKessler, BMWendt, MKDas, CFlaherty, DPDysregulation of the ubiquitin-proteasome systems is a hallmark of various disease states including neurodegenerative diseases and cancer. Ubiquitin C-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme, is expressed primarily in the central nervous system under normal physiological conditions, however, is considered an oncogene in various cancers, including melanoma, lung, breast, and lymphoma. Thus, UCHL1 inhibitors could serve as a viable treatment strategy against these aggressive cancers. Herein, we describe a covalent fragment screen that identified the chloroacetohydrazide scaffold as a covalent UCHL1 inhibitor. Subsequent optimization provided an improved fragment with single-digit micromolar potency against UCHL1 and selectivity over the closely related UCHL3. The molecule demonstrated efficacy in cellular assays of metastasis. Additionally, we report a ligand-bound crystal structure of the most potent molecule in complex with UCHL1, providing insight into the binding mode and information for future optimization. |
| spellingShingle | Imhoff, RD Patel, R Safdar, MH Jones, HBL Pinto-Fernandez, A Vendrell, I Chen, H Muli, CS Krabill, AD Kessler, BM Wendt, MK Das, C Flaherty, DP Covalent fragment screening and optimization identifies the chloroacetohydrazide scaffold as inhibitors for ubiquitin C-terminal hydrolase L1 |
| title | Covalent fragment screening and optimization identifies the chloroacetohydrazide scaffold as inhibitors for ubiquitin C-terminal hydrolase L1 |
| title_full | Covalent fragment screening and optimization identifies the chloroacetohydrazide scaffold as inhibitors for ubiquitin C-terminal hydrolase L1 |
| title_fullStr | Covalent fragment screening and optimization identifies the chloroacetohydrazide scaffold as inhibitors for ubiquitin C-terminal hydrolase L1 |
| title_full_unstemmed | Covalent fragment screening and optimization identifies the chloroacetohydrazide scaffold as inhibitors for ubiquitin C-terminal hydrolase L1 |
| title_short | Covalent fragment screening and optimization identifies the chloroacetohydrazide scaffold as inhibitors for ubiquitin C-terminal hydrolase L1 |
| title_sort | covalent fragment screening and optimization identifies the chloroacetohydrazide scaffold as inhibitors for ubiquitin c terminal hydrolase l1 |
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