Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, PR China.
J Med Chem. 2021 May 13;64(9):6179-6197. doi: 10.1021/acs.jmedchem.1c00246. Epub 2021 May 3.
Overexpression of ATP binding cassette (ABC) transporters, including P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), is an important factor leading to multidrug resistance (MDR) in cancer treatments. Three subclasses of dual inhibitors of P-gp and BCRP were designed based on the active moieties of BCRP inhibitors, tyrosine kinase inhibitors, and P-gp inhibitors, of which compound possessed low cytotoxicity, high reversal potency, and good lipid distribution coefficient. also increased the accumulation of Adriamycin (ADM) and Mitoxantrone (MX), blocked Rh123 efflux, and made no change in the protein expression of P-gp and BCRP. Importantly, coadministration of can significantly improve the oral bioavailability of paclitaxel (PTX). It was also demonstrated that significantly inhibited the growth of K562/A02 xenograft tumors by increasing the sensitivity of ADM . In summary, has the potential to overcome MDR caused by P-gp and BCRP and to improve the oral bioavailability of PTX.
三磷酸腺苷结合盒（ABC）转运蛋白的过度表达，包括 P-糖蛋白（P-gp）和乳腺癌耐药蛋白（BCRP），是导致癌症治疗中多药耐药（MDR）的一个重要因素。基于 BCRP 抑制剂、酪氨酸激酶抑制剂和 P-gp 抑制剂的活性部分，设计了三种 P-gp 和 BCRP 的双重抑制剂亚类，其中化合物 具有低细胞毒性、高逆转效力和良好的脂分布系数。还增加了阿霉素（ADM）和米托蒽醌（MX）的积累，阻断 Rh123 外排，并且对 P-gp 和 BCRP 的蛋白表达没有改变。重要的是，联合使用 可以显著提高紫杉醇（PTX）的口服生物利用度。研究还表明， 通过增加 ADM 的敏感性， 显著抑制了 K562/A02 异种移植肿瘤的生长。综上所述， 有可能克服由 P-gp 和 BCRP 引起的多药耐药，并提高 PTX 的口服生物利用度。
