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Ref Type Journal Article
PMID (29866747)
Authors Zhu D, Xu S, Deyanat-Yazdi G, Peng SX, Barnes LA, Narla RK, Tran T, Mikolon D, Ning Y, Shi T, Jiang N, Raymon HK, Riggs JR, Boylan JF
Title 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.
Journal Molecular cancer therapeutics
Vol 17
Issue 8
Date 2018 Aug
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
CC-671 CC-671 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
CC-671 MPS1 Inhibitor 25 CC-671 inhibits CLK2 and TTK (MPS1), potentially resulting in decreased proliferation and increased apoptosis of tumor cells and reduced tumor growth (PMID: 29866747).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown triple-receptor negative breast cancer not applicable CC-671 Preclinical - Pdx & cell culture Actionable In a preclinical study, CC-671 induced apoptosis and inhibited growth of triple-negative breast cancer (TNBC) cell lines in culture, and inhibited tumor growth in TNBC cell line and patient-derived xenograft (PDX) models (PMID: 29866747). 29866747