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Ref Type Journal Article
PMID (29545334)
Authors Patel H, Periyasamy M, Sava GP, Bondke A, Slafer BW, Kroll SHB, Barbazanges M, Starkey R, Ottaviani S, Harrod A, Aboagye EO, Buluwela L, Fuchter MJ, Barrett AGM, Coombes RC, Ali S
Title ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment.
Journal Molecular cancer therapeutics
Vol 17
Issue 6
Date 2018 06
URL
Abstract Text 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 (ER)-α. Here we describe a new, orally bioavailable CDK7 inhibitor, ICEC0942. It selectively inhibits CDK7, with an IC50 of 40 nmol/L; 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 and 0.3 μmol/L. In xenografts of both breast and colorectal cancers, the drug has substantial antitumor effects. In addition, 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. Mol Cancer Ther; 17(6); 1156-66. ©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
ICEC0942 ICEC0942 2 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
ICEC0942 CT 7001|CT7001|CT-7001 CDK7 Inhibitor 13 ICEC0942 (CT7001) is an orally available and selective CDK7 inhibitor that prevents Cdk7 phosphorylation to induce cell cycle arrest and apoptosis (PMID: 29545334, PMID: 32150405).
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 breast cancer not applicable ICEC0942 Preclinical - Cell line xenograft Actionable In a preclinical study, ICEC0942 induced growth arrest of breast cancer cells in culture and in cell line xenograft models (PMID: 29545334). 29545334
Unknown unknown colorectal cancer not applicable ICEC0942 Preclinical - Cell line xenograft Actionable In a preclinical study, ICEC0942 induced growth arrest of colorectal cancer cells in culture and in cell line xenograft models (PMID: 29545334). 29545334