Synthesis and Structure–Activity Relationship Studies of N-Benzyl-2-phenylpyrimidin-4-amine Derivatives as Potent USP1/UAF1 Deubiquitinase Inhibitors with Anticancer Activity against Nonsmall Cell Lung Cancer
| Autor: | Junjun Chen, Mark A. Villamil, Anton Simeonov, Qin Liang, Zhihao Zhuang, Hongmao Sun, David J. Maloney, Thomas S. Dexheimer, Edward H. Kerns, Diane K. Luci, Andrew S. Rosenthal, Ajit Jadhav |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Lung Neoplasms
DNA damage Druggability Antineoplastic Agents Article Deubiquitinating enzyme 03 medical and health sciences Structure-Activity Relationship 0302 clinical medicine Ubiquitin Carcinoma Non-Small-Cell Lung Cell Line Tumor Proliferating Cell Nuclear Antigen Drug Discovery medicine Structure–activity relationship Humans 030304 developmental biology 0303 health sciences biology Chemistry Arabidopsis Proteins Ubiquitination Cancer Nuclear Proteins medicine.disease Small molecule 3. Good health Pyrimidines Cell culture 030220 oncology & carcinogenesis biology.protein Cancer research Molecular Medicine Ubiquitin-Specific Proteases |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Deregulation of ubiquitin conjugation or deconjugation has been implicated in the pathogenesis of many human diseases including cancer. The deubiquitinating enzyme USP1 (ubiquitin-specific protease 1), in association with UAF1 (USP1-associated factor 1), is a known regulator of DNA damage response and has been shown as a promising anticancer target. To further evaluate USP1/UAF1 as a therapeutic target, we conducted a quantitative high throughput screen of >400000 compounds and subsequent medicinal chemistry optimization of small molecules that inhibit the deubiquitinating activity of USP1/UAF1. Ultimately, these efforts led to the identification of ML323 (70) and related N-benzyl-2-phenylpyrimidin-4-amine derivatives, which possess nanomolar USP1/UAF1 inhibitory potency. Moreover, we demonstrate a strong correlation between compound IC50 values for USP1/UAF1 inhibition and activity in nonsmall cell lung cancer cells, specifically increased monoubiquitinated PCNA (Ub-PCNA) levels and decreased cell survival. Our results establish the druggability of the USP1/UAF1 deubiquitinase complex and its potential as a molecular target for anticancer therapies. |
| Databáze: | OpenAIRE |
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