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.

Abstract

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.

• Authors: Dan Zhu, Shuichan Xu, Gordafaried Deyanat-Yazdi, Sophie X Peng, Leo A Barnes, Rama Krishna Narla, Tam Tran, David Mikolon, Yuhong Ning, Tao Shi, Ning Jiang, Heather K Raymon, Jennifer R Riggs, John F Boylan
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 17 Issue 8 Pg. 1727-1738 (08 2018) ISSN: 1538-8514 [Electronic] United States
• PMID: 29866747 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Cell Cycle Proteins
• Protein Kinase Inhibitors
• Protein-Tyrosine Kinases
• Protein Serine-Threonine Kinases
• TTK protein, human

Topics

• Animals
• Cell Cycle Proteins (antagonists & inhibitors, metabolism)
• Cell Line, Tumor
• Female
• Humans
• Mice
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Protein Serine-Threonine Kinases (metabolism)
• Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
• Synthetic Lethal Mutations (drug effects)
• Triple Negative Breast Neoplasms (drug therapy)