CDK7 inhibitors as anticancer drugs

Georgina P Sava, Hailing Fan, R Charles Coombes, Lakjaya Buluwela, Simak Ali, Georgina P Sava, Hailing Fan, R Charles Coombes, Lakjaya Buluwela, Simak Ali

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 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.

Keywords: CDK inhibitors; CDK7; Cancer therapy; Cell cycle; Combination therapy; Transcription.

Conflict of interest statement

RCC and SA are named as inventors on CDK7 inhibitor patents and own shares in Carrick Therapeutics.

Figures

Fig. 1
Fig. 1
Overview of the regulation of CAK and the role of CDK7 in regulating the cell cycle (a) and transcription (b). CAK = CDK activating kinase, CDK = cyclin-dependent kinase, CK2 = protein kinase CK2, G1 = gap phase 1, G2 = gap phase 2, M = mitosis, P = phosphate, PKCι = protein kinase C iota, Pol II = RNA polymerase II, S = synthesis, TFIIH = transcription factor II H
Fig. 2
Fig. 2
Super-enhancer-driven gene deregulation in cancer can be targeted by CDK7 inhibitors. The super-enhancer landscape in normal cells (a) becomes deregulated in cancer (b), leading to altered gene expression. CDK7 inhibitors preferentially reduce gene expression driven by super-enhancers in cancer cells compared with normal cells (A and B). CDK7i = CDK7 inhibitor
Fig. 3
Fig. 3
Chemical structures of selected inhibitors that target CDK7. Chemical structures of non-specific inhibitors of CDK7 (a) and selective inhibitors of CDK7 (b). (The chemical structures of QS1189 and SY-5609 have not been disclosed)

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