Imidazo[1,2-a]Pyridine Derivatives as Novel Dual-Target Inhibitors of ABCB1 and ABCG2 for Reversing Multidrug Resistance,Journal of Medicinal Chemistry

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Imidazo[1,2-a]Pyridine Derivatives as Novel Dual-Target Inhibitors of ABCB1 and ABCG2 for Reversing Multidrug Resistance
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-02-13 , DOI: 10.1021/acs.jmedchem.2c01862
Hui Li _{1,

2} , Sheng-Lie Zhang _{1,

2} , Yan-Han Jia ₃ , Qian Li _{1,

2} , Zi-Wen Feng _{1,

2} , Shi-Duo Zhang _{1,

2} , Wei Zheng _{1,

2} , Ye-Ling Zhou _{1,

2} , Lin-Lin Li _{1,

2} , Xue-Chun Liu _{1,

2} , Ya-Qiong Chen ₃ , Hui Peng ₃ , Qi-Dong You _{1,

2} , Xiao-Li Xu _{1,

2}

Affiliation

ABCB1 and ABCG2 are the important ATP-binding cassette (ABC) transporters associated with multidrug resistance (MDR). Herein, we designed a series of imidazo[1,2-a]pyridine derivatives as dual-target inhibitors of ABCB1 and ABCG2 through the scaffold hopping strategy. Compound Y22 displayed potential efflux function inhibitory toward both ABCB1 and ABCG2 (reversal fold: ABCB1 = 8.35 and ABCG2 = 2.71) without obvious cytotoxicity. Y22 also enhanced the potency of antiproliferative drugs in vitro. Mechanistic studies demonstrated that Y22 slightly suppressed ATPase activity but did not affect the protein expression of ABCB1 or ABCG2. Notably, Y22 exhibited negligible CYP3A4 inhibition and enhanced the antiproliferative activity of adriamycin in vivo by restoring the sensitivity of resistant cells. Thus, Y22 may be effective clinically in combination with common chemotherapy agents. In summary, Y22 is a potential dual-target inhibitor that reverses MDR by blocking the efflux function of ABCB1 and ABCG2.

中文翻译：

咪唑并 [1,2-a] 吡啶衍生物作为 ABCB1 和 ABCG2 的新型双靶点抑制剂用于逆转多药耐药性

ABCB1 和 ABCG2 是与多药耐药性 (MDR) 相关的重要 ATP 结合盒 (ABC) 转运蛋白。在此，我们通过支架跳跃策略设计了一系列咪唑并[1,2- a ]吡啶衍生物作为ABCB1和ABCG2的双靶点抑制剂。化合物Y22显示出对 ABCB1 和 ABCG2 的潜在流出功能抑制（逆转倍数：ABCB1 = 8.35 和 ABCG2 = 2.71），没有明显的细胞毒性。Y22还在体外增强了抗增殖药物的效力。机理研究表明，Y22略微抑制 ATP 酶活性，但不影响 ABCB1 或 ABCG2 的蛋白表达。值得注意的是，Y22表现出可忽略不计的 CYP3A4 抑制作用，并通过恢复耐药细胞的敏感性来增强体内阿霉素的抗增殖活性。因此，Y22可能在临床上与常见的化疗药物联合使用是有效的。总之，Y22是一种潜在的双靶点抑制剂，可通过阻断 ABCB1 和 ABCG2 的外排功能来逆转 MDR。

更新日期：2023-02-13

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