CDK7 inhibitors as anticancer drugs
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CDK7 inhibitors as anticancer drugs Georgina P. Sava 1 & Hailing Fan 1 & R. Charles Coombes 1 & Lakjaya Buluwela 1 & Simak Ali 1
# The Author(s) 2020
Abstract 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 superenhancer-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. Keywords CDK7 . CDK inhibitors . Cell cycle . Transcription . Cancer therapy . Combination therapy
1 Introduction Cyclin-dependent kinase 7 (CDK7), along with cyclin H and MAT1, comprises the CDK-activating kinase (CAK), which provides the T-loop phosphorylation required for activation of CDKs 1,2, 4 and 6, which drive cell cycle progression (Table 1, Fig. 1a) [1–4]. CAK also has a role in the regulation of transcription, as a component of the general transcription factor TFIIH. At active gene promoters, CDK7 phosphorylates the C-terminal domain (CTD) of RNA polymerase II (Pol II), at serine 5 (Ser5), to facilitate transcription initiation (Table 1, Fig. 1b) [5–7]. CDK7 also phosphorylates CDK9, which in turn phosphorylates the Pol II CTD at Ser2, to drive transcription elongation [8]. The activities of a variety of transcription factors, including p53 [9, 10], retinoic acid receptor [11–13], oestrogen receptor [14, 15] and androgen receptor
* Simak Ali [email protected] 1
Division of Cancer, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, London, U
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