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Synthetic Lethal Strategy Identifies a Potent and Selective TTK and CLK2 Inhibitor for Treatment of Triple-negative Breast Cancer with a Compromised G1/S Checkpoint
Molecular Cancer Therapeutics ( IF 5.3 ) Pub Date : 2018-06-04 , DOI: 10.1158/1535-7163.mct-17-1084
Dan Zhu 1 , Shuichan Xu 1 , Gordafaried Deyanat-Yazdi 1 , Sophie X. Peng 2 , Leo A. Barnes 2 , Rama Krishna Narla 2 , Tam Tran 1 , David Mikolon 1 , Yuhong Ning 3 , Tao Shi 3 , Ning Jiang 1 , Heather K. Raymon 2 , Jennifer R. Riggs 4 , John F. Boylan 1
Affiliation  

Historically, phenotypic-based drug discovery has yielded a high percentage of novel drugs while uncovering new tumor biology. CC-671 was discovered using a phenotypic screen for compounds that preferentially induced apoptosis in triple-negative breast cancer cell lines while sparing luminal breast cancer cell lines. Detailed in vitro kinase profiling shows CC-671 potently and selectively inhibits two kinases—TTK and CLK2. Cellular mechanism of action studies demonstrate that CC-671 potently inhibits the phosphorylation of KNL1 and SRp75, direct TTK and CLK2 substrates, respectively. Furthermore, CC-671 causes mitotic acceleration and modification of pre-mRNA splicing leading to apoptosis, consistent with cellular TTK and CLK inhibition. Correlative analysis of genomic and potency data against a large panel of breast cancer cell lines identifies breast cancer cells with a dysfunctional G1–S checkpoint as more sensitive to CC-671, suggesting synthetic lethality between G1–S checkpoint and TTK/CLK2 inhibition. Furthermore, significant in vivo CC-671 efficacy was demonstrated in two cell line–derived and one patient tumor-derived xenograft models of triple-negative breast cancer (TNBC) following weekly dosing. These findings are the first to demonstrate the unique inhibitory combination activity of a dual TTK/CLK2 inhibitor that preferably kills TNBC cells and shows synthetic lethality with a compromised G1–S checkpoint in breast cancer cell lines. On the basis of these data, CC-671 was moved forward for clinical development as a potent and selective TTK/CLK2 inhibitor in a subset of patients with TNBC. Mol Cancer Ther; 17(8); 1727–38. ©2018 AACR.

中文翻译:

合成致死策略确定了一种有效且选择性的 TTK 和 CLK2 抑制剂,用于治疗具有受损 G1/S 检查点的三阴性乳腺癌

从历史上看,基于表型的药物发现在发现新的肿瘤生物学的同时产生了很高比例的新药。CC-671 是通过对化合物的表型筛选发现的,这些化合物优先诱导三阴性乳腺癌细胞系中的细胞凋亡,同时不影响管腔乳腺癌细胞系。详细的体外激酶分析显示 CC-671 有效且选择性地抑制两种激酶 - TTK 和 CLK2。细胞作用机制研究表明,CC-671 可有效抑制 KNL1 和 SRp75 的磷酸化,分别直接抑制 TTK 和 CLK2 底物。此外,CC-671 导致有丝分裂加速和前 mRNA 剪接修饰,导致细胞凋亡,与细胞 TTK 和 CLK 抑制一致。针对一大组乳腺癌细胞系的基因组和效力数据的相关分析发现,具有功能失调的 G1-S 检查点的乳腺癌细胞对 CC-671 更敏感,表明 G1-S 检查点和 TTK/CLK2 抑制之间的合成致死率。此外,在每周给药后,在两种细胞系来源和一种患者肿瘤来源的三阴性乳腺癌 (TNBC) 异种移植模型中证明了显着的体内 CC-671 功效。这些发现首次证明了双 TTK/CLK2 抑制剂的独特抑制组合活性,该抑制剂可优先杀死 TNBC 细胞,并在乳腺癌细胞系中 G1-S 检查点受损的情况下显示合成致死率。在这些数据的基础上,CC-671 作为一种有效的、选择性的 TTK/CLK2 抑制剂在 TNBC 患者子集中进行临床开发。摩尔癌症治疗; 17(8); 1727-38 年。©2018 AACR。
更新日期:2018-06-04
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