Targeting CDK7 in oncology: The avenue forward

Abstract

Cyclin-dependent kinase (CDK) 7 is best characterized for the ability to regulate biological processes, including the cell cycle and gene transcription. Abnormal CDK7 activity is observed in various tumours and represents a driving force for tumourigenesis. Therefore, CDK7 may be an appealing target for cancer treatment. Whereas, the enthusiasm for CDK7-targeted therapeutic strategy is mitigated due to the widely possessed belief that this protein is essential for normal cells. Indeed, the fact confronts the consensus. This is the first review to introduce the role of CDK7 in pan-cancers via a combined analysis of comprehensive gene information and (pre)clinical research results. We also discuss the recent advances in protein structure and summarize the understanding of mechanisms underlying CDK7 function. These endeavours highlight the pivotal roles of CDK7 in tumours and may contribute to the development of effective CDK7 inhibitors within the strategy of structure-based drug discovery for cancer therapy.

Introduction

All living organisms on Earth must cope with constant changes in the extracellular and intracellular environment. The development of elegant cell cycle pathways and transcriptional programs allows cells to respond to stimuli by regulating cell division and gene expression, which are critical for cell proliferation and growth (Malumbres, 2014). Cyclin-dependent protein kinases (CDKs) are identified as core components of these fundamental processes, for which a Nobel Prize was awarded in 2001 (Whittaker, Mallinger, Workman, & Clarke, 2017). Uncontrolled proliferative ability and gene dysregulation are hallmarks of cancer (Zielinska & Katanaev, 2019). For two decades, targeting CDKs to block cell division and promote apoptosis has gained more attention in cancer treatment (Pack, Daigh, Chung, & Meyer, 2021; Parua & Fisher, 2020).

As a prominent member of the CDK family, CDK7 in combination with cyclin H and MAT1, serves as the CDK-activating kinase complex (CAK) to phosphorylate the cell cycle-associated CDKs and the carboxy-terminal repeat domain (CTD) of RNA polymerase II (Pol II) (Chen et al., 2021; Rengachari, Schilbach, Aibara, Dienemann, & Cramer, 2021). These two distinct roles have been elegantly portrayed and placed CDK7 under the spotlight of oncology. Amplification of CDK7 has been observed in several cancer types and is correlated with poor prognosis (Patel et al., 2016; Zeng et al., 2021). In last several years, significant efforts from the pharmaceutical industry and academia have ensured CDK7 of seat among the appealing targets for cancer therapy (Wei et al., 2021; Zhang et al., 2020; Zhang et al., 2020; Zhang et al., 2020). Specifically, a series of selective inhibitors of CDK7 have been developed with effective pro-apoptotic and anti-tumour activity, revealing that CDK7 affects the transcription of key cancer-dependent genes, thereby leading to abnormal activation of classical cancer pathways (Kalan et al., 2017; Zhou et al., 2019). Currently, two active phase I clinical trials involving CDK7 inhibitors (SY-5609 and CT7001) have been conducted in patients with breast cancer, pancreatic cancer, and advanced solid malignancies (including small cell lung cancer (SCLC) and ovarian cancer) (Marineau et al., 2022; Sava, Fan, Coombes, Buluwela, & Ali, 2020). To date, two studies have elucidated the structure of CDK7 and its relevant complex, CAK. In 2004, the first X-ray protein structure of human CDK7-ATP was outlined (Lolli, Lowe, Brown, & Johnson, 2004). CAK was structurally unrevealed until 2020 (Greber et al., 2020). The resolution of the cryo-electron microscopy (cryo-EM) structure of human CDK7-cyclin H-MAT1-ATPγS was determined at 2.8 Å. In the same year, cryo-EM structures of human CAK in complex with THZ1 and CT7001 were determined at 3.3 Å and 2.5 Å, respectively (Greber et al., 2020; Greber, Remis, Ali, & Nogales, 2021). These refined structures offer vital insights into CDK7 function and may provide an avenue for structure-based drug discovery.

This review highlights the recent advances in the structure and function of CDK7 and analyses CDK7 gene-related information in various cancer types as well as in classical tumour signalling pathways using bioinformatics tools. Moreover, it focuses on the new CDK7 blockers for cancer therapy and briefly discusses CDK7 blockers that can be developed in the future. This is the first review to display an overview painting of CDK7, which confirms the promising status of CDK7 as an anti-tumour target via a combined analysis of comprehensive gene information and (pre)clinical research results.