ISO-66, a novel inhibitor of macrophage migration, shows efficacy in melanoma and colon cancer models.
ISO-66, a novel inhibitor of macrophage migration, shows efficacy in melanoma and colon cancer models.
复制标题
DOI：
10.3892/ijo.2014.2551
复制
发表时间：
2014-10
影响因子：
5.2
通讯作者：
Al-Abed Y
中科院分区：
文献类型：
--
作者：
Ioannou K;Cheng KF;Crichlow GV;Birmpilis AI;Lolis EJ;Tsitsilonis OE;Al-Abed Y
巨噬细胞移动抑制因子（macrophage migration inhibitor factor，MIF）是一种多效性促炎细胞因子，在肿瘤的进展和转移中起重要作用，是一种很有前途的抗癌药物靶点。许多MIF灭活策略已被证明在延迟癌症生长方面是成功的。在这里，我们报告的合成ISO-66，一种新型的，高度稳定的，小分子的MIF抑制剂，ISO-1的类似物具有改进的特性。MIF：ISO-66共晶体结构表明，ISO-66连接MIF的互变异构酶活性位点，该活性位点先前已被证明在其生物学功能中起重要作用。在体外，ISO-66增强了特异性和非特异性抗癌免疫应答，而ISO-66在已建立的同基因黑色素瘤或结肠癌小鼠中的长期给药是无毒的，并导致肿瘤负荷显著降低。随后的小鼠脾细胞的体外分析显示，观察到的肿瘤生长速率的降低可能是由ISO-66诱导的抗肿瘤反应性效应细胞的选择性体内扩增介导的。与体内采用的其他MIF灭活策略相比，ISO-66的抗癌活性被证明具有相等或更好的功效。我们的研究结果表明，通过高度特异性和稳定的化合物（如ISO-66）靶向MIF可能对癌症治疗和刺激抗癌免疫反应有效。
Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory cytokine, which possesses a contributing role in cancer progression and metastasis and, thus, is now considered a promising anticancer drug target. Many MIF-inactivating strategies have proven successful in delaying cancer growth. Here, we report on the synthesis of ISO-66, a novel, highly stable, small-molecule MIF inhibitor, an analog of ISO-1 with improved characteristics. The MIF:ISO-66 co-crystal structure demonstrated that ISO-66 ligates the tautomerase active site of MIF, which has previously been shown to play an important role in its biological functions. In vitro, ISO-66 enhanced specific and non-specific anticancer immune responses, whereas prolonged administration of ISO-66 in mice with established syngeneic melanoma or colon cancer was non-toxic and resulted in a significant decrease in tumor burden. Subsequent ex vivo analysis of mouse splenocytes revealed that the observed decrease in tumor growth rates was likely mediated by the selective in vivo expansion of antitumor-reactive effector cells induced by ISO-66. Compared to other MIF-inactivating strategies employed in vivo, the anticancer activity of ISO-66 is demonstrated to be of equal or better efficacy. Our findings suggest that targeting MIF, via highly specific and stable compounds, such as ISO-66, may be effective for cancer treatment and stimulation of anticancer immune responses.
登录
查看更多内容
DOI：
10.1084/jem.190.10.1375
发表时间：
1999-11-15
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hudson JD;Shoaibi MA;Maestro R;Carnero A;Hannon GJ;Beach DH
通讯作者：
Beach DH
影响因子：
8.8
作者：
Girard, E.;Strathdee, C.;Trueblood, E.;Queva, C.
通讯作者：
Queva, C.
影响因子：
3
作者：
Chuang CC;Chuang YC;Chang WT;Chen CC;Hor LI;Huang AM;Choi PC;Wang CY;Tseng PC;Lin CF
通讯作者：
Lin CF
DOI：
10.1107/s0907444998003254
发表时间：
1998-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Brunger, AT;Adams, PD;Warren, GL
通讯作者：
Warren, GL
影响因子：
4.8
作者：
Piette, Caroline;Deprez, Manuel;Munaut, Carine
通讯作者：
Munaut, Carine