Functional Characterization of CFI-400945, a Polo-like Kinase 4 Inhibitor, as a Potential Anticancer Agent
Functional Characterization of CFI-400945, a Polo-like Kinase 4 Inhibitor, as a Potential Anticancer Agent
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DOI：
10.1016/j.ccr.2014.05.006
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发表时间：
2014-08-11
期刊：
影响因子：
50.3
通讯作者：
Mak, Tak W.
中科院分区：
文献类型：
--
作者：
Mason, Jacqueline M.;Lin, Dan Chi-Chia;Mak, Tak W.
通过将RNAi筛选和基因表达分析相结合的系统方法，Plk4被确定为一个有前景的治疗靶点。一项药物发现计划最终产生了CFI-400945，一种有效和选择性的Plk4抑制剂。用CFI-400945处理的癌细胞表现出与Plk4激酶抑制一致的效果，包括中心粒复制失调、有丝分裂缺陷和细胞死亡。对荷人癌移植瘤小鼠口服CFI-400945可显著抑制肿瘤生长，剂量可耐受。与PTEN野生型移植瘤相比，PTEN缺陷型移植瘤体内抗肿瘤活性增强。我们的发现为CFI-400945在实体瘤患者中的临床评估提供了理论基础，尤其是那些PTEN缺陷的患者。
PLK4 was identified as a promising therapeutic target through a systematic approach that combined RNAi screening with gene expression analysis in human breast cancers and cell lines. A drug discovery program culminated in CFI-400945, a potent and selective PLK4 inhibitor. Cancer cells treated with CFI-400945 exhibit effects consistent with PLK4 kinase inhibition, including dysregulated centriole duplication, mitotic defects, and cell death. Oral administration of CFI-400945 to mice bearing human cancer xenografts results in the significant inhibition of tumor growth at doses that are well tolerated. Increased antitumor activity in vivo was observed in PTEN-deficient compared to PTEN wild-type cancer xenografts. Our findings provide a rationale for the clinical evaluation of CFI-400945 in patients with solid tumors, in particular those deficient in PTEN.