Imperial College London
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Professor Matthew J. Fuchter

Faculty of Natural Sciences, Department of Chemistry

Professor of Chemistry
 
 
 
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Contact

 

+44 (0)20 7594 5815m.fuchter

 
 
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Location

 

110DMolecular Sciences Research HubWhite City Campus

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Summary

 

Publications

Citation

BibTex format

@article{Ali:2018:10.1158/1535-7163.MCT-16-0847,
author = {Ali, S and Patel, H and Periyasamy, M and Sava, G and Bondke, A and Slafer, BW and Kroll, SHB and Barbazanges, MV and Starkey, RG and Ottaviani, S and Harrod, AE and Aboagye, EO and Buluwela, L and Fuchter, MJ and Barrett, AGM and Coombes, C},
doi = {10.1158/1535-7163.MCT-16-0847},
journal = {Molecular Cancer Therapeutics},
title = {ICEC0942, an orally bioavailable selective inhibitor of CDK7 for cancer treatment},
url = {http://dx.doi.org/10.1158/1535-7163.MCT-16-0847},
year = {2018}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Recent reports indicate that some cancer types are especially sensitive to transcription inhibition, suggesting that targeting the transcriptional machinery provides new approaches to cancer treatment. Cyclin-dependent kinase (CDK)7 is necessary for transcription, and acts by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (PolII) to enable transcription initiation. CDK7 additionally regulates the activities of a number of transcription factors, including Estrogen receptor-α (ER). Here we describe a new, orally bioavailable CDK7 inhibitor, ICEC0942. It selectively inhibits CDK7, with an IC50 of 40nM; IC50 values for CDK1, CDK2, CDK5 and CDK9 were 45-, 15-, 230- and 30-fold higher. In vitro studies show that a wide range of cancer types are sensitive to CDK7 inhibition with GI50 values ranging between 0.2-0.3 µM. In xenografts of both breast and colorectal cancers, the drug has substantial anti-tumor effects. Additionally, combination therapy with tamoxifen showed complete growth arrest of ER-positive tumor xenografts. Our findings reveal that CDK7 inhibition provides a new approach, especially for ER-positive breast cancer and identify ICEC0942 as a prototype drug with potential utility as a single agent or in combination with hormone therapies for breast cancer. ICEC0942 may also be effective in other cancers that display characteristics of transcription factor addiction, such as acute leukaemia, and small-cell lung cancer.
AU  - Ali,S
AU  - Patel,H
AU  - Periyasamy,M
AU  - Sava,G
AU  - Bondke,A
AU  - Slafer,BW
AU  - Kroll,SHB
AU  - Barbazanges,MV
AU  - Starkey,RG
AU  - Ottaviani,S
AU  - Harrod,AE
AU  - Aboagye,EO
AU  - Buluwela,L
AU  - Fuchter,MJ
AU  - Barrett,AGM
AU  - Coombes,C
DO  - 10.1158/1535-7163.MCT-16-0847
PY  - 2018///
SN  - 1535-7163
TI  - ICEC0942, an orally bioavailable selective inhibitor of CDK7 for cancer treatment
T2  - Molecular Cancer Therapeutics
UR  - http://dx.doi.org/10.1158/1535-7163.MCT-16-0847
UR  - http://hdl.handle.net/10044/1/57863
ER  -
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