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Preclinical studies of the triazolo[1,5-a]pyrimidine derivative WS-716 as a highly potent,specific and orally active P-glycoprotein(P-gp)inhibitor

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Acta Pharmaceutica Sinica B 2022年第8期12卷 3263-3280页

作者： Sai-Qi Wang Qiu-Xu Teng Shuai Wang Zi-Ning Lei Hui-Hui Hu Hui-Fang Lv Bei-Bei Chen Jian-Zheng Wang Xiao-Jing Shi Wei-Feng Xu Hong-Min Liu Xiao-Bing Chen Zhe-Sheng Chen Bin Yu Department of Oncology the Affiliated Cancer Hospital of Zhengzhou UniversityHenan Cancer HospitalHenan Cancer InstituteZhengzhou 450008China School of Pharmaceutical Sciences Zhengzhou UniversityZhengzhou 450001China State Key Laboratory of Esophageal Cancer Prevention&Treatment Zhengzhou UniversityZhengzhou 450052China College of Pharmacy and Health Sciences St.John’s UniversityQueensNY 11439USA Laboratory Animal Center Academy of Medical ScienceZhengzhou UniversityZhengzhou 450052China

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.

关键词： Multidrug resistance(MDR) ATP-binding cassette P-gp inhibitors Triazolo[1,5-a]pyrimidine Drug combination Preclinical studies Cancer therapy

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ABC efflux transporters at blood-central nervous system barriers and their implications for treating spinal cord disorders

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Neural Regeneration Research 2020年第7期15卷 1235-1242页

作者： Liam M. Koehn Department of Pharmacology and Therapeutics the University of Melbourne

The barriers present in the interfaces between the blood and the central nervous system form a major hurdle for the pharmacological treatment of central nervous system injuries and diseases.The family of ATP-binding cassette(ABC)transporters has been widely studied regarding efflux of medications at blood-central nervous system barriers.These efflux transporters include P-glycoprotein(abcb1),‘breast cancer resistance protein'(abcg2)and the various‘multidrug resistance-associated proteins'(abccs).Understanding which efflux transporters are present at the blood-spinal cord,blood-cerebrospinal fluid and cerebrospinal fluid-spinal cord barriers is necessary to determine their involvement in limiting drug transfer from blood to the spinal cord tissue.Recent developments in the blood-brain barrier field have shown that barrier systems are dynamic and the profile of barrier defenses can alter due to conditions such as age,disease and environmental challenge.This means that a true understanding of ABC efflux transporter expression and localization should not be one static value but instead a range that represents the complex patient subpopulations that exist.In the present review,the blood-central nervous system barrier literature is discussed with a focus on the impact of ABC efflux transporters on:(i)protecting the spinal cord from adverse effects of systemically directed drugs,and(ii)limiting centrally directed drugs from accessing their active sites within the spinal cord.

关键词： ABC transporters ATP-binding cassette BCRP blood-brain barrier blood-spinal cord barrier efflux MRP P-glycoprotein PGP spinal cord injury

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新型P-gp抑制剂的设计、合成及生物活性研究

新型P-gp抑制剂的设计、合成及生物活性研究

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2011年全国药物化学学术会议——药物的源头创新

作者：谷小珂唐孝波张奕华中国药科大学新药研究中心

＜正＞肿瘤化疗的最大障碍是肿瘤细胞对药物产生多药耐药性（multidrug resistance,MDR）。MDR产生的机制复杂多样,一些atp结合式（ATP-binding cassette,ABC）跨膜转运蛋白包括P-糖蛋白（P-glycoprotein,P-gp）、多药耐药相关蛋白（MRP... 详细信息

＜正＞肿瘤化疗的最大障碍是肿瘤细胞对药物产生多药耐药性（multidrug resistance,MDR）。MDR产生的机制复杂多样,一些atp结合式（ATP-binding cassette,ABC）跨膜转运蛋白包括P-糖蛋白（P-glycoprotein,P-gp）、多药耐药相关蛋白（MRP1）、乳腺癌耐药蛋白（BCRP）等在肿瘤细胞中过度表达,是肿瘤细胞产生多药耐药现象的重要

关键词：多药耐药性（MDR） ATP-binding cassette P-糖蛋白 P-gP抑制剂

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