Discovery of a non-toxic [1,2,4]triazolo[1,5-a]pyrimidin-7-one (WS-10) that modulates ABCB1-mediated multidrug resistance (MDR)

Liming Chang; Mengwu Xiao; Linlin Yang; Shuai Wang; Sai-Qi Wang; Andreas Bender; Aixi Hu; Zhe-Sheng Chen; Bin Yu; Hong-Min Liu

doi:10.1016/j.bmc.2018.08.021

Discovery of a non-toxic [1,2,4]triazolo[1,5-a]pyrimidin-7-one (WS-10) that modulates ABCB1-mediated multidrug resistance (MDR)

Bioorg Med Chem. 2018 Oct 1;26(18):5006-5017. doi: 10.1016/j.bmc.2018.08.021. Epub 2018 Aug 18.

Authors

Liming Chang¹, Mengwu Xiao², Linlin Yang³, Shuai Wang¹, Sai-Qi Wang¹, Andreas Bender⁴, Aixi Hu⁵, Zhe-Sheng Chen⁶, Bin Yu⁷, Hong-Min Liu⁸

Affiliations

¹ School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Co-Innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou 450001, China; Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Zhengzhou 450001, China.
² Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK; College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China.
³ Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
⁴ Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
⁵ College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China.
⁶ College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
⁷ School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Co-Innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou 450001, China; Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Zhengzhou 450001, China; College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, China; Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou 510033, China. Electronic address: zzuyubin@hotmail.com.
⁸ School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Co-Innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou 450001, China; Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Zhengzhou 450001, China. Electronic address: liuhm@zzu.edu.cn.

PMID: 30150104
DOI: 10.1016/j.bmc.2018.08.021

Abstract

Multidrug resistance (MDR) has been shown to reduce the effectiveness of chemotherapy. Strategies to overcoming MDR have been widely explored in the last decades, leading to a generation of numerous small molecules targeting ABC and MRP transporters. Among the ABC family, ABCB1 plays key roles in the development of drug resistance and is the most well studied. In this work, we report the discovery of a non-toxic [1,2,4]triazolo[1,5-a]pyrimidin-7-one (WS-10) from our structurally diverse in-house compound collection that selectively modulates ABCB1-mediated multidrug resistance. WS-10 enhanced the intracellular accumulation of paclitaxel in SW620/Ad300 cells, but did not affect the expression of ABCB1 Protein and ABCB1 localization. The cellular thermal shift assay (CETSA) showed that WS-10 was able to bind to ABCB1, which could be responsible for the reversal effect of WS-10 toward paclitaxel and doxorubicin in SW620/Ad300 cells. Docking simulations were performed to show the possible binding modes of WS-10 within ABCB1 transporter. To conclude, WS-10 could be used as a template for designing new ABCB1 modulators to overcome ABCB1-mediated multidrug resistance.

Keywords: ABC transporters; ABCB1; Multidrug resistance (MDR); Triazolo [1,5-a]pyrimidin-7-one.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B / drug effects
ATP Binding Cassette Transporter, Subfamily B / physiology
Antineoplastic Agents, Phytogenic / pharmacology
Azoles / chemistry
Azoles / pharmacology*
Cell Line, Tumor
Drug Resistance, Multiple / drug effects*
Humans
Inhibitory Concentration 50
Paclitaxel / pharmacology
Pyrimidines / chemistry
Pyrimidines / pharmacology*

Substances

(1,2,4)triazolo(1,5-a)pyrimidin-7-one
ABCB1 protein, human
ATP Binding Cassette Transporter, Subfamily B
Antineoplastic Agents, Phytogenic
Azoles
Pyrimidines
Paclitaxel