OSI-930 analogues as novel reversal agents for ABCG2-mediated multidrug resistance.
OSI-930 analogues as novel reversal agents for ABCG2-mediated multidrug resistance.
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DOI：
10.1016/j.bcp.2012.06.019
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发表时间：
2012-09-15
影响因子：
5.8
通讯作者：
Chen, Zhe-Sheng
中科院分区：
文献类型：
--
作者：
Kuang, Ye-Hong;Patel, Jay P.;Sodani, Kamlesh;Wu, Chung-Pu;Liao, Li-Qiu;Patel, Atish;Tiwari, Amit K.;Dai, Chun-Ling;Chen, Xiang;Fu, Li-Wu;Ambudkar, Suresh V.;Korlipara, Vijaya L.;Chen, Zhe-Sheng
OSI-930是一种双重c-Kit和KDR酪氨酸激酶抑制剂，据报道已经在晚期实体瘤患者中进行了I期剂量递增研究。设计并合成了15个吡啶基和苯基的OSI-930类似物。对这些化合物的广泛筛选导致发现硝基吡基和邻硝基苯基类似物VKJP1和VKJP3可有效逆转ABC亚家族G成员2 （ABCG2）转运体介导的多药耐药（MDR）。VKJP1和VKJP3使表达ABCG2的细胞对既定的ABCG2底物（包括米托沙酮、cn -38和阿霉素）呈浓度依赖性致敏，但对非ABCG2底物顺铂不敏感。然而，它们无法逆转ABCB1或abcc1介导的MDR，这表明它们对ABCG2具有选择性。Western blotting分析ABCG2的表达，发现VKJP1和VKJP3在72 h内都没有显著改变ABCG2蛋白的表达。[3H]-米托蒽醌积累研究表明，VKJP1和VKJP3增加了ABCG2的底物[3H]-米托蒽醌在细胞内的积累。VKJP1和VKJP3也显著抑制ABCG2膜囊对[3H]-甲氨蝶呤的转运。重要的是，VKJP1和VKJP3都能有效地刺激ABCG2的atp酶活性，并抑制该转运体被其底物[125I]-碘arylazidoprazosin光亲和标记。结果表明，VKJP1和VKJP3通过与ABCG2的底物结合位点直接相互作用特异性抑制ABCG2的功能。因此，VKJP1和VKJP3代表了一类减少ABCG2过表达肿瘤耐多药的新药物。
OSI-930, a dual c-Kit and KDR tyrosine kinase inhibitor, is reported to have undergone a Phase I dose escalation study in patients with advanced solid tumors. A series of fifteen pyridyl and phenyl analogues of OSI-930 were designed and synthesized. Extensive screening of these compounds led to the discovery that nitropyridyl and ortho-nitrophenyl analogues, VKJP1 and VKJP3, were effective in reversing ABC subfamily G member 2 (ABCG2) transporter-mediated multidrug resistance (MDR). VKJP1 and VKJP3 significantly sensitized ABCG2-expressing cells to established substrates of ABCG2 including mitoxantrone, SN-38, and doxorubicin in a concentration-dependent manner, but not to the non-ABCG2 substrate cisplatin. However, they were unable to reverse ABCB1- or ABCC1-mediated MDR indicating their selectivity for ABCG2. Western blotting analysis was performed to evaluate ABCG2 expression and it was found that neither VKJP1 nor VKJP3 significantly altered ABCG2 protein expression for up to 72 h. [3H]-mitoxantrone accumulation study demonstrated that VKJP1 and VKJP3 increased the intracellular accumulation of [3H]-mitoxantrone, a substrate of ABCG2. VKJP1 and VKJP3 also remarkably inhibited the transport of [3H]-methotrexate by ABCG2 membrane vesicles. Importantly, both VKJP1 and VKJP3 were efficacious in stimulating the activity of ATPase of ABCG2 and inhibited the photoaffinity labeling of this transporter by its substrate [125I]-iodoarylazidoprazosin. The results suggested that VKJP1 and VKJP3, specifically inhibit the function of ABCG2 through direct interaction with its substrate binding site(s). Thus VKJP1 and VKJP3 represent a new class of drugs for reducing MDR in ABCG2 over-expressing tumors.
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影响因子：
11.2
作者：
Dai CL;Tiwari AK;Wu CP;Su XD;Wang SR;Liu DG;Ashby CR Jr;Huang Y;Robey RW;Liang YJ;Chen LM;Shi CJ;Ambudkar SV;Chen ZS;Fu LW
通讯作者：
Fu LW
影响因子：
5.7
作者：
Petti, F;Thelemann, A;Haley, JD
通讯作者：
Haley, JD
影响因子：
2.7
作者：
Patel, Jay P.;Kuang, Ye-Hong;Korlipara, Vijaya L.
通讯作者：
Korlipara, Vijaya L.
DOI：
10.1073/pnas.95.26.15665
发表时间：
1998-12-22
影响因子：
11.1
作者：
Doyle, LA;Yang, WD;Ross, DD
通讯作者：
Ross, DD
影响因子：
11.2
作者：
Houghton, PJ;Germain, GS;Traxler, P
通讯作者：
Traxler, P