Imperial College London
Alternate

ProfessorCharlesCoombes

Faculty of Medicine, Department of Surgery & Cancer

Emeritus Professor of Medical Oncology
 
 
 
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Contact

 

+44 (0)20 7594 2135c.coombes

 
 
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Assistant

 

Mrs Suzy Ford +44 (0)20 7594 2135

 
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Location

 

145ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Sava:2020:10.1007/s10555-020-09885-8,
author = {Sava, GP and Fan, H and Coombes, RC and Buluwela, L and Ali, S},
doi = {10.1007/s10555-020-09885-8},
journal = {Cancer and Metastasis Reviews},
pages = {805--823},
title = {CDK7 inhibitors as anticancer drugs},
url = {http://dx.doi.org/10.1007/s10555-020-09885-8},
volume = {39},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Cyclin-dependent kinase 7 (CDK7), along with cyclin H and MAT1, forms the CDK-activating complex (CAK), which directs progression through the cell cycle via T-loop phosphorylation of cell cycle CDKs. CAK is also a component of the general transcription factor, TFIIH. CDK7-mediated phosphorylation of RNA polymerase II (Pol II) at active gene promoters permits transcription. Cell cycle dysregulation is an established hallmark of cancer, and aberrant control of transcriptional processes, through diverse mechanisms, is also common in many cancers. Furthermore, CDK7 levels are elevated in a number of cancer types and are associated with clinical outcomes, suggestive of greater dependence on CDK7 activity, compared with normal tissues. These findings identify CDK7 as a cancer therapeutic target, and several recent publications report selective CDK7 inhibitors (CDK7i) with activity against diverse cancer types. Preclinical studies have shown that CDK7i cause cell cycle arrest, apoptosis and repression of transcription, particularly of super-enhancer-associated genes in cancer, and have demonstrated their potential for overcoming resistance to cancer treatments. Moreover, combinations of CDK7i with other targeted cancer therapies, including BET inhibitors, BCL2 inhibitors and hormone therapies, have shown efficacy in model systems. Four CDK7i, ICEC0942 (CT7001), SY-1365, SY-5609 and LY3405105, have now progressed to Phase I/II clinical trials. Here we describe the work that has led to the development of selective CDK7i, the current status of the most advanced clinical candidates, and discuss their potential importance as cancer therapeutics, both as monotherapies and in combination settings. ClinicalTrials.gov Identifiers: NCT03363893; NCT03134638; NCT04247126; NCT03770494.
AU  - Sava,GP
AU  - Fan,H
AU  - Coombes,RC
AU  - Buluwela,L
AU  - Ali,S
DO  - 10.1007/s10555-020-09885-8
EP  - 823
PY  - 2020///
SN  - 0167-7659
SP  - 805
TI  - CDK7 inhibitors as anticancer drugs
T2  - Cancer and Metastasis Reviews
UR  - http://dx.doi.org/10.1007/s10555-020-09885-8
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000531116500003&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://link.springer.com/article/10.1007%2Fs10555-020-09885-8
UR  - http://hdl.handle.net/10044/1/80918
VL  - 39
ER  -
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