Novel Inhibitors of Rac 1 in Metastatic Breast Cancer
Novel Inhibitors of Rac 1 in Metastatic Breast Cancer
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发表时间：
2010
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通讯作者：
E. Hernández;Alina De La Mota-Peynado;S. Dharmawardhane;C. Vlaar
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作者：
E. Hernández;Alina De La Mota-Peynado;S. Dharmawardhane;C. Vlaar
作者通信地址：波多黎各大学医学院生物化学系Surangani Dharmawardhane博士，邮政信箱365067，邮编：PR00936。电话：787-758-2525分机。1630/1610·传真：787-274-8724·电子邮件：su.d@upr.edu&Cornelis P.Vlaar PhD，波多黎各大学医学院药学系，电话：(787)758-2525转5432/1236·传真：(787)767-2796·E-mail：cornelis.vlaar@upr.edu目的：Rho家族GTP酶是控制信号通路调节多种细胞功能的分子开关。Rho家族成员rac1在肿瘤发生、肿瘤进展、侵袭和转移等多个方面发挥重要作用。Rac蛋白在大多数侵袭性人类癌症中不会发生突变，但被发现过度活跃或过度表达。由于Rho GTP酶被鸟嘌呤核苷酸交换因子(GEF)激活，因此抑制RAC与其GEF的相互作用是阻断RAC激活的一种有针对性的策略。方法：NSC23766是一种Rac1与部分GEF相互作用的抑制剂，其IC50值太高，不能用于治疗，因此需要更有效的抑制剂。因此，我们通过对中心嘧啶环上的取代基进行修饰，合成了新的NSC23766衍生物，并测试了它们的rac1抑制活性。结果：与NSC23766相比，几个NSC23766衍生物对肿瘤细胞的rac1活性具有更高的抑制效率(比NSC23766高20-50%)。新化合物对正常乳腺上皮细胞无毒，在抑制细胞迁移以及减少细胞扩散和片状脂膜延伸方面比NSC23766更有效(60%-70%)，片状脂膜是由RAC调节的有助于癌症侵袭的细胞功能。结论：根据研究结果，我们得出结论，这些新化合物有望进一步发展成为乳腺癌侵袭性进展的小分子抑制剂。[P R Health Sci J 2010；4：348-356]
Author correspondence to: Surangani Dharmawardhane PhD, Department of Biochemistry, School of Medicine, Medical Sciences Campus University of Puerto Rico, PO Box 365067, San Juan, PR00936. Tel: 787-758-2525 ext. 1630/1610 • Fax: 787-274-8724 • E-mail: su.d@upr.edu & Cornelis P. Vlaar PhD, Department of Pharmaceutical Sciences, School of Pharmacy, Medical Sciences Campus University of Puerto Rico, Tel: (787) 758-2525 ext. 5432/1236 • Fax: (787) 767-2796 • E-mail: cornelis.vlaar@upr.edu Objective: Rho family GTPases are molecular switches that control signaling pathways regulating a myriad of cellular functions. Rac1, a Rho family member, plays a critical role in several aspects of tumorigenesis, cancer progression, invasion, and metastasis. Rac proteins are not mutated in most invasive human cancers but are found to be overactive or over-expressed. Since Rho GTPases are activated by guanine nucleotide exchange factors (GEFs), inhibition of the interaction of Rac with its GEFs is a targeted strategy for blocking Rac activation. Methods: The IC50 of NSC23766, an inhibitor of the interaction of Rac1 with a subset of GEFs, is too high for therapeutic use and more efficacious inhibitors are desired. Therefore, we initiated the synthesis of new derivatives of NSC23766 with modifications of the substituents connected to the central pyrimidine ring, and tested their Rac1 inhibitory activity. Results: Several of the NSC23766 derivatives were shown to inhibit Rac1 activity of cancer cells with higher efficiency (20-50% more) than NSC23766. The new compounds are not toxic to normal mammary epithelial cells and are more efficient (60-70%) than NSC23766 in inhibiting cell migration and reducing cell spreading and extension of lamellipodia, cell functions regulated by Rac that contribute to cancer invasion. Conclusion: Based on the results, we conclude that the novel compounds show promise of further development as small molecule inhibitors of invasive breast cancer progression. [P R Health Sci J 2010;4:348-356]