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Zhang L, Shen J, Yin Y, et al. Identifying Cell Cycle Modulators That Selectively Target ARID1A Deficiency Using High-Throughput Image-Based Screening. SLAS Discov. 2017;22(7):813-826doi: 10.1177/2472555217698942.
Zhang, L., Shen, J., Yin, Y., Peng, Y., Wang, L., Hsieh, H. J., Shen, Q., Brown, P. H., Tao, K., Uray, I. P., & Peng, G. (2017). Identifying Cell Cycle Modulators That Selectively Target ARID1A Deficiency Using High-Throughput Image-Based Screening. SLAS discovery : advancing life sciences R & D, 22(7), 813-826. https://doi.org/10.1177/2472555217698942
Zhang, Lihong, et al. "Identifying Cell Cycle Modulators That Selectively Target ARID1A Deficiency Using High-Throughput Image-Based Screening." SLAS discovery : advancing life sciences R & D vol. 22,7 (2017): 813-826. doi: https://doi.org/10.1177/2472555217698942
Zhang L, Shen J, Yin Y, Peng Y, Wang L, Hsieh HJ, Shen Q, Brown PH, Tao K, Uray IP, Peng G. Identifying Cell Cycle Modulators That Selectively Target ARID1A Deficiency Using High-Throughput Image-Based Screening. SLAS Discov. 2017 Aug;22(7):813-826. doi: 10.1177/2472555217698942. Epub 2017 Mar 15. PMID: 28297605; PMCID: PMC5921049.
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SLAS Discov. 2017 Aug;22(7):813-826. doi: 10.1177/2472555217698942. Epub 2017 Mar 15.

Identifying Cell Cycle Modulators That Selectively Target ARID1A Deficiency Using High-Throughput Image-Based Screening.

SLAS discovery : advancing life sciences R & D

Lihong Zhang, Jianfeng Shen, Yuping Yin, Yang Peng, Lulu Wang, Hui-Ju Hsieh, Qian Shen, Powel H Brown, Kaixiong Tao, Ivan P Uray, Guang Peng

Affiliations

  1. 1 Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China.
  2. 2 Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  3. 3 Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China.
  4. 4 Department of Clinical Oncology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

PMID: 28297605 PMCID: PMC5921049 DOI: 10.1177/2472555217698942

Abstract

ARID1A, a component of the chromatin remodeling complex SWI/SNF, is an evolutionarily conserved complex that uses the energy of adenosine triphosphate hydrolysis to remodel chromatin structure and functions as a master regulator of gene transcription. Recent genomic studies have revealed that ARID1A is one of the most frequently mutated genes in human cancers. However, therapeutic approaches that selectively target ARID1A-mutant tumors are not yet clinically available. Our previous study showed that ARID1A facilitates chromatin response and cell cycle checkpoint activation after DNA damage. Therefore, an ARID1A deficiency may result in therapeutic vulnerabilities in cell cycle modulators. The goals of our study were to develop a novel screening approach, based on fluorescent ubiquitination-based cell cycle indicators (FUCCI), and to identify chemical agents that can selectively modulate the cell cycle transition in ARID1A-deficient cancer cells. Using this high-throughput assay, we screened 2643 compounds and identified six potential chemical modulators that can selectively modulate the cell cycle in ARID1A-deficient cells; these agents may be useful for developing new therapeutics for ARID1A-mutant tumors. In summary, our study demonstrates that FUCCI cell-based high-content screening is a powerful and effective approach for identifying cell cycle modulators and can be applied to multigenotypic screening for targeted cancer therapeutics.

Keywords: ARID1A; FUCCI; cell cycle modulator; high-throughput drug screening

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