{"title":"Discovery of N-Benzylpiperidinol derivatives as USP7 inhibitors against Hematology","authors":"","doi":"10.1016/j.bioorg.2024.107807","DOIUrl":null,"url":null,"abstract":"<div><p>USP7 has been recognized as a potential target for the treatment of hematologic malignancies by stabilizing multiple cancer-relevant proteins. Nevertheless, drug-like USP7 inhibitors are still lacking. Herein, compound <strong>J21</strong> (USP7 IC<sub>50</sub>: 41.35 ± 2.16 nM) was discovered based on the structure of <strong>L55</strong> and its co-crystal complex with USP7. Additionally, <strong>J21</strong> exhibited greater metabolic stability (<em>T</em><sub>1/2</sub>: 1.25 h, C<sub>max</sub>: 394.1 ± 48.3 ng/mL, and AUC<sub>0-t</sub>: 597.8 ± 44.8 ng/mL∙h) compared to <strong>L55</strong>. These findings may further pave the way for the development of USP7 inhibitors for the treatment of hematologic malignancies.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5000,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic Chemistry","FirstCategoryId":"92","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0045206824007120","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
USP7 has been recognized as a potential target for the treatment of hematologic malignancies by stabilizing multiple cancer-relevant proteins. Nevertheless, drug-like USP7 inhibitors are still lacking. Herein, compound J21 (USP7 IC50: 41.35 ± 2.16 nM) was discovered based on the structure of L55 and its co-crystal complex with USP7. Additionally, J21 exhibited greater metabolic stability (T1/2: 1.25 h, Cmax: 394.1 ± 48.3 ng/mL, and AUC0-t: 597.8 ± 44.8 ng/mL∙h) compared to L55. These findings may further pave the way for the development of USP7 inhibitors for the treatment of hematologic malignancies.
期刊介绍：
Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry.
For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature.
The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.
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