Preclinical studies of the triazolo1,5-apyrimidine derivative WS-716 as a highly potent, specific and orally active P-glycoprotein (P-gp) inhibitor.
10.1016/j.apsb.2022.03.023
- Author:
Sai-Qi WANG
1
;
Qiu-Xu TENG
2
;
Shuai WANG
3
;
Zi-Ning LEI
2
;
Hui-Hui HU
1
;
Hui-Fang LV
1
;
Bei-Bei CHEN
1
;
Jian-Zheng WANG
1
;
Xiao-Jing SHI
4
;
Wei-Feng XU
1
;
Hong-Min LIU
3
;
Xiao-Bing CHEN
1
;
Zhe-Sheng CHEN
2
;
Bin YU
3
Author Information
1. Department of Oncology, the Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Henan Cancer Institute, Zhengzhou 450008, China.
2. College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
3. School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
4. Laboratory Animal Center, Academy of Medical Science, Zhengzhou University, Zhengzhou 450052, China.
- Publication Type:Journal Article
- Keywords:
ATP-Binding cassette;
Cancer therapy;
Drug combination;
Multidrug resistance (MDR);
P-gp inhibitors;
Preclinical studies;
Triazolo[1,5-a]pyrimidine
- From:
Acta Pharmaceutica Sinica B
2022;12(8):3263-3280
- CountryChina
- Language:English
-
Abstract:
Multidrug resistance (MDR) is the main cause of clinical treatment failure and poor prognosis in cancer. Targeting P-glycoprotein (P-gp) has been regarded as an effective strategy to overcome MDR. In this work, we reported our preclinical studies of the triazolo[1,5-a]pyrimidine-based compound WS-716 as a highly potent, specific, and orally active P-gp inhibitor. Through direct binding to P-gp, WS-716 inhibited efflux function of P-gp and specifically reversed P-gp-mediated MDR to paclitaxel (PTX) in multiple resistant cell lines, without changing its expression or subcellular localization. WS-716 and PTX synergistically inhibited formation of colony and 3D spheroid, induced apoptosis and cell cycle arrest at G2/M phase in resistant SW620/Ad300 cells. In addition, WS-716 displayed minimal effect on the drug-metabolizing enzyme cytochrome P4503A4 (CYP3A4). Importantly, WS-716 increased sensitivity of both pre-clinically and clinically derived MDR tumors to PTX in vivo with the T/C value of 29.7% in patient-derived xenograft (PDX) models. Relative to PTX treatment alone, combination of WS-716 and PTX caused no obvious adverse reactions. Taken together, our preclinical studies revealed therapeutic promise of WS-716 against MDR cancer, the promising data warrant its further development for cancer therapy.
