School of Pharmaceutical Sciences & Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China.
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China.
J Med Chem. 2021 Oct 14;64(19):14895-14911. doi: 10.1021/acs.jmedchem.1c01452. Epub 2021 Sep 21.
The major drawbacks of P-glycoprotein (P-gp) inhibitors at the clinical stage make the development of new P-gp inhibitors challenging and desirable. In this study, we reported our structure-activity relationship studies of 4-indolyl quinazoline, which led to the discovery of a highly effective and orally active P-gp inhibitor, . effectively reversed multidrug resistance (MDR) to paclitaxel and colchicine in SW620/AD300 and HEK293T-ABCB1 cells. bound directly to P-gp, did not alter expression or subcellular localization of P-gp in SW620/AD300 cells, but increased the intracellular accumulation of paclitaxel. Furthermore, stimulated the P-gp ATPase activity and had moderate inhibition against CYP3A4. Significantly, oral administration of in combination with paclitaxel achieved much stronger antitumor activity in a xenograft model bearing SW620/Ad300 cells than either drug alone. Taken together, our data demonstrate that is a promising P-gp inhibitor capable of overcoming MDR and represents a unique scaffold for the development of new P-gp inhibitors.
在临床阶段，P-糖蛋白（P-gp）抑制剂的主要缺点使得新型 P-gp 抑制剂的开发具有挑战性和必要性。在本研究中，我们报告了我们对 4-吲哚基喹唑啉的构效关系研究，这导致了一种高效、口服活性的 P-gp 抑制剂的发现，即 。 有效地逆转了紫杉醇和秋水仙碱在 SW620/AD300 和 HEK293T-ABCB1 细胞中的多药耐药性（MDR）。 直接与 P-gp 结合，不改变 SW620/AD300 细胞中 P-gp 的表达或亚细胞定位，但增加了紫杉醇的细胞内积累。此外， 刺激了 P-gp ATP 酶活性，对 CYP3A4 有适度的抑制作用。值得注意的是， 与紫杉醇联合口服给药在携带 SW620/Ad300 细胞的异种移植模型中实现了比单独使用任何一种药物更强的抗肿瘤活性。总之，我们的数据表明， 是一种有前途的 P-gp 抑制剂，能够克服 MDR，并代表了开发新型 P-gp 抑制剂的独特支架。
