Compound C620-0696, a new potent inhibitor targeting BPTF, the chromatin-remodeling factor in non-small-cell lung cancer

doi:10.1007/s11684-019-0694-8

Front. Med.

2020, Vol. 14

Issue (1) : 60-67 https://doi.org/10.1007/s11684-019-0694-8

RESEARCH ARTICLE

Compound C620-0696, a new potent inhibitor targeting BPTF, the chromatin-remodeling factor in non-small-cell lung cancer

Jiahui Xu¹, Qianqian Wang¹, Elaine Lai Han Leung^1,^2,³, Ying Li¹, Xingxing Fan¹, Qibiao Wu¹(

), Xiaojun Yao¹(

), Liang Liu¹(

)

¹. State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR) 519020, China
². Respiratory Medicine Department, Taihe Hospital, Hubei University of Medicine, Shiyan 236600, China
³. Department of Thoracic Surgery, Guangzhou Institute of Respiratory Health and State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510182, China

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Abstract

Bromodomain PHD-finger transcription factor (BPTF) is the largest subunit of the nucleosome remodeling factor and plays an important role in chromatin remodeling for gene activation through its association with histone acetylation or methylation. BPTF is also involved in oncogene transcription in diverse progressions of cancers. Despite clinical trials for inhibitors of bromodomain and extra-terminal family proteins in human cancers, no potent and selective inhibitor targeting the BPTF bromodomain has been discovered. In this study, we identified a potential inhibitor, namely, C620-0696, by computational docking modeling to target bromodomain. Results of biolayer interferometry revealed that compound C620-0696 exhibited high binding affinity to the BPTF bromodomain. Moreover, C620-0696 was cytotoxic in BPTF with a high expression of non-small-cell lung cancer (NSCLC) cells. It suppressed the expression of the BPTF target gene c-MYC, which is known as an oncogenic transcriptional regulator in various cancers. C620-0696 also partially inhibited the migration and colony formation of NSCLC cells owing to apoptosis induction and cell cycle blockage. Thus, our study presents an effective strategy to target a bromodomain factor-mediated tumorigenesis in cancers with small molecules, supporting further exploration of the use of these inhibitors in oncology.

Keywords BPTF small molecule epigenetics non-small-cell lung cancer

Corresponding Author(s): Qibiao Wu,Xiaojun Yao,Liang Liu

Just Accepted Date: 18 April 2019 Online First Date: 21 May 2019 Issue Date: 02 March 2020

Cite this article:

Jiahui Xu,Qianqian Wang,Elaine Lai Han Leung, et al. Compound C620-0696, a new potent inhibitor targeting BPTF, the chromatin-remodeling factor in non-small-cell lung cancer[J]. Front. Med., 2020, 14(1): 60-67.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-019-0694-8
https://academic.hep.com.cn/fmd/EN/Y2020/V14/I1/60

Fig.1 (A) Chemical structure of C620-0696. (B) Determination of the binding affinity of the BPTF bromodomain with C620-0696 by BLI assay. The binding affinity (K_D) of the bromodomain for C620-0696 was determined by the rate constants of K_on = 4.78 × 10² L·mol⁻¹·s⁻¹ and K_off = 1.70 × 10 ⁻²s⁻¹. (C) The detailed binding mode between C620-0696 and the BPTF bromodomain. Green dashed lines represent hydrogen bonds.

Fig.2 (A) BPTF expression was analyzed by Western blot in BEAS-2B, A549, and H358 cell lines. (B, C) Cell viability was measured in A549 and H358 cells treated with C620-0696 at 3, 6, 9, 12 mmol/L for 72 h. (D) The IC₅₀ value was calculated in A549 and H358 cells treated with C620-0696. All data were presented as mean±SD. *P<0.05, **P<0.01, and ***P<0.001.

Fig.3 (A, C) Motility of C620-0696-treated cells or control cells captured after 24 and 48 h post injury, respectively. Dashed yellow lines show the images of a representative wound (10×). (B, D) Rate of wound healing of A549 and H358 cells. All data were presented as mean±SD. *P<0.05.

Fig.4 (A, B) A549 and H358 cells of colony formation assay data after treatment with C620-0696 (Control, 1, 1.5, and 3 mmol/L ).(C,D) Statistical analysis of colony formation assay. All data were presented as mean±SD. *P<0.05, **P<0.01, and ***P<0.001.

Fig.5 (A) H358 cells were treated with C620-0696 at Control, 3, 6, and 9 mmol/L for 24 h. Western blot was used to detect the expression levels of PARP-1, c-MYC, and cyclin D1, while GAPDH was used as the loading control. (B) Statistical analysis of colony formation assay. All data were presented as mean±SD. *P<0.05, **P<0.01.

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