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ICEC0942, an orally bioavailable selective inhibitor of CDK7 for cancer treatment

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Title: ICEC0942, an orally bioavailable selective inhibitor of CDK7 for cancer treatment
Authors: Ali, S
Patel, H
Periyasamy, M
Sava, G
Bondke, A
Slafer, BW
Kroll, SHB
Barbazanges, MV
Starkey, RG
Ottaviani, S
Harrod, AE
Aboagye, EO
Buluwela, L
Fuchter, MJ
Barrett, AGM
Coombes, C
Item Type: Journal Article
Abstract: 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.
Issue Date: 15-Mar-2018
Date of Acceptance: 6-Mar-2018
URI: http://hdl.handle.net/10044/1/64250
DOI: https://dx.doi.org/10.1158/1535-7163.MCT-16-0847
ISSN: 1535-7163
Publisher: American Association for Cancer Research
Journal / Book Title: Molecular Cancer Therapeutics
Replaces: http://hdl.handle.net/10044/1/57863
10044/1/57863
Copyright Statement: © 2018, American Association for Cancer Research.
Sponsor/Funder: Cancer Research UK
Engineering & Physical Science Research Council (EPSRC)
Cancer Research UK
Cancer Research UK
Cancer Research Technology Ltd
Funder's Grant Number: 6944
EP/F008856/1
C37/A9335
C37/A12011
TEPO-4005156
Keywords: 1112 Oncology And Carcinogenesis
1115 Pharmacology And Pharmaceutical Sciences
Oncology & Carcinogenesis
Publication Status: Published online
Appears in Collections:Division of Surgery
Chemistry
Division of Cancer
Faculty of Medicine
Faculty of Natural Sciences



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