作者: Lin, Lizhu ; Lei, Zi‐Ning ; Zou, Chang ; Wang, Jing‐Quan ; Chen, Zhe‐Sheng ; Teng, Qiu‐Xu ; Yang, Yuqi ; Wu, Zhuo‐Xun ; Wang, Guangsuo ; Sun, Lingling

AbstractOne pivotal factor that leads to multidrug resistance (MDR) is the overexpression of ABCG2. Therefore, tremendous effort has been devoted to the search of effective reversal agents to overcome ABCG2‐mediated MDR. CC‐671 is a potent and selective inhibitor of both TTK (human protein kinase monopolar spindle 1 [hMps1]) and CDC like kinase 2 (CLK2). It represents a new class of cancer therapeutic drugs. In this study, we show that CC‐671 is an effective ABCG2 reversal agent that enhances the efficacy of chemotherapeutic drugs in ABCG2‐overexpressing lung cancer cells. Mechanistic studies show that the reversal effect of CC‐671 is primarily attributed to the inhibition of the drug efflux activity of ABCG2, which leads to an increased intracellular level of chemotherapeutic drugs. In addition, CC‐671 does not alter the protein expression or subcellular localization of ABCG2. The computational molecule docking analysis suggests CC‐671 has high binding affinity to the drug‐binding site of ABCG2. In conclusion, we reveal the interaction between CC‐671 and ABCG2, providing a rationale for the potential combined use of CC‐671 with ABCG2 substrate to overcome MDR.

2018-08-01·Molecular Cancer Therapeutics2区 · 医学

Synthetic Lethal Strategy Identifies a Potent and Selective TTK and CLK1/2 Inhibitor for Treatment of Triple-Negative Breast Cancer with a Compromised G1–S Checkpoint

2区 · 医学

Article

作者: Shi, Tao ; Tran, Tam ; Boylan, John F. ; Ning, Yuhong ; Deyanat-Yazdi, Gordafaried ; Zhu, Dan ; Barnes, Leo A. ; Peng, Sophie X. ; Mikolon, David ; Xu, Shuichan ; Narla, Rama Krishna ; Raymon, Heather K. ; Jiang, Ning ; Riggs, Jennifer R.

AbstractHistorically, 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.

2017-11-09·Journal of Medicinal Chemistry1区 · 医学

The Discovery of a Dual TTK Protein Kinase/CDC2-Like Kinase (CLK2) Inhibitor for the Treatment of Triple Negative Breast Cancer Initiated from a Phenotypic Screen

1区 · 医学

Article

作者: Narla, Rama Krishna ; Chamberlain, Philip P. ; Miller, Terra ; Elsner, Jan ; Robinson, Dale ; Zhu, Dan ; Canan, Stacie S. ; Tang, Yang ; Riggs, Jennifer R. ; Katz, Jason ; Erdman, Paul ; Bahmanyar, Sogole ; Pagarigan, Barbra ; Boylan, John F. ; Harris, Roy ; Tran, Tam ; Delker, Silvia ; Chen, Ming ; Cashion, Dan ; Calabrese, Andrew ; Moghaddam, Mehran F. ; LeBrun, Laurie ; Barnes, Leo ; Deyanat-Yazdi, Gordafaried ; Leftheris, Katerina ; Tehrani, Lida ; Peng, Xiaohui ; Nagy, Mark ; Huang, Dehua

Triple negative breast cancer (TNBC) remains a serious unmet medical need with discouragingly high relapse rates. We report here the synthesis and structure-activity relationship (SAR) of a novel series of 2,4,5-trisubstituted-7H-pyrrolo[2,3-d]pyrimidines with potent activity against TNBC tumor cell lines. These compounds were discovered from a TNBC phenotypic screen and possess a unique dual inhibition profile targeting TTK (mitotic exit) and CLK2 (mRNA splicing). Design and optimization, driven with a TNBC tumor cell assay, identified potent and selective compounds with favorable in vitro and in vivo activity profiles and good iv PK properties. This cell-based driven SAR produced compounds with strong single agent in vivo efficacy in multiple TNBC xenograft models without significant body weight loss. These data supported the nomination of CC-671 into IND-enabling studies as a single agent TNBC therapy.

100 项与 CC-671 相关的药物交易

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