Zhu Jiewen, Chen Hongyuan, Guo Xuning Emily, Qiu Xiao-Long, Hu Chun-Mei, Chamberlin A Richard, Lee Wen-Hwa
Department of Biological Chemistry, School of Medicine, USA.
Department of Biological Chemistry, School of Medicine, USA; Taiwan Genomic Research Center, Academia Sinica, Taipei, Taiwan.
Eur J Med Chem. 2015;96:196-208. doi: 10.1016/j.ejmech.2015.04.021. Epub 2015 Apr 9.
RAD51 recombinase plays a critical role for cancer cell proliferation and survival. Targeting RAD51 is therefore an attractive strategy for treating difficult-to-treat cancers, e.g. triple negative breast cancers which are often resistant to existing therapeutics. To this end, we have designed, synthesized and evaluated a panel of new RAD51 inhibitors, denoted IBR compounds. Among these compounds, we have identified a novel small molecule RAD51 inhibitor, IBR120, which exhibited a 4.8-fold improved growth inhibition activity in triple negative human breast cancer cell line MBA-MD-468. IBR120 also inhibited the proliferation of a broad spectrum of other cancer cell types. Approximately 10-fold difference between the IC50 values in normal and cancer cells were observed. Moreover, IBR120 was capable of disrupting RAD51 multimerization, impairing homologous recombination repair, and inducing apoptotic cell death. Therefore, these novel RAD51 inhibitors may serve as potential candidates for the development of pharmaceutical strategies against difficult-to-treat cancers.
RAD51重组酶在癌细胞增殖和存活中起着关键作用。因此，靶向RAD51是治疗难治性癌症（如通常对现有疗法耐药的三阴性乳腺癌）的一种有吸引力的策略。为此，我们设计、合成并评估了一组新的RAD51抑制剂，即IBR化合物。在这些化合物中，我们鉴定出一种新型小分子RAD51抑制剂IBR120，它在三阴性人乳腺癌细胞系MBA-MD-468中表现出提高了4.8倍的生长抑制活性。IBR120还抑制了多种其他癌细胞类型的增殖。在正常细胞和癌细胞的IC50值之间观察到约10倍的差异。此外，IBR120能够破坏RAD51多聚化，损害同源重组修复，并诱导凋亡性细胞死亡。因此，这些新型RAD51抑制剂可能成为开发针对难治性癌症的药物策略的潜在候选物。
