Acknowledgements This work was supported in part by a

Acknowledgements This work was supported in part by a Scholarship Fund for Young Researchers by the Promotion and Mutual Aid Corporation for Private (2017 to S.K.), research grant from Japan Rett Syndrome Support Organization (2018 to S.K.), and MEXT-Supported Program for the Strategic Research Foundation at Private Universities (2015–2019 to T.I.). We thank Rachel James, Ph.D., from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript. We thank Mr. M. Fukui and Mr. T. Matsubara for technical assistance.
Introduction The notion of the opioid receptor antagonist and its regulatory restriction points was first proposed in the 1970s and early 1980s. The machinery components associated with this process were identified and characterized through many genetic and biochemical studies, mainly in yeast, but also in sea urchin, xenopus, and eventually higher eukaryotic cells (Nurse, 2000). The core of this work resulted in the identification of the CDKs and their partner cyclins for which the Nobel Prize in Physiology and Medicine was awarded to Hartwell, Hunt and Nurse in 2001. The regulation of the growth and division of cells came to the attention of the biomedical research community when it became clear that unconstrained proliferation, in part due to a loss of cell cycle regulation, played a key role in the initiation and progression of cancer. More recently, sustained proliferation through the deregulation of cell cycle control has been recognized as one of the key hallmarks of cancer (Hanahan & Weinberg, 2011), and our understanding of how specific CDKs regulate transcription and maintain the oncogenic state has advanced considerably. This has led to considerable efforts to develop CDK inhibitors as cancer therapeutics, which is the subject of this review. Here we will review the role of CDKs in cancer and particularly those for which inhibitors have currently been identified. These inhibitors include the early non-selective inhibitors that suffered from toxicity and poor efficacy, but more importantly the more recent developments in selective CDK inhibitors that have led to the approval of palbociclib for the treatment of breast cancer.
Cell cycle regulation by CDKs The cell cycle has 5 distinct phases during which cells either have the capacity to grow (G1 and G2 phases), replicate their DNA (S phase), divide by mitosis (M phase) or can cease to proliferate and enter quiescence (G0 phase) (Fig. 2). Cell cycle progression is governed by the activities of particular CDKs and interaction with their regulatory cyclin partners (Sherr, 1996, van den Heuvel and Harlow, 1993). The function and role of the key individual CDKs that regulate cell cycle progression are described in detail in the sections below.
Transcriptional regulation by CDKs The polymerase responsible for transcribing all protein-coding genes is RNA polymerase II. RNA polymerase II catalyzes the transcription of histone-associated genomic DNA, which is wrapped around nucleosomes and can be covalently modified to regulate the access of the transcriptional apparatus to the DNA (Li, Carey, & Workman, 2007). For gene-specific transcription to take place RNA polymerase II has to be recruited to, and then exit, the gene's promoter that is then and followed by productive transcription that elongates the mRNA. This is a complex process requiring chromatin modification, the recruitment of sequence-specific transcription factors and post-translation modification of the transcriptional machinery. RNA polymerase II is unique among the cellular polymerases as its largest subunit has a C-terminal domain (CTD) with an extended repeat comprised of a YSPTSPS heptapeptide that is present in a copy number ranging from 26 in budding yeast to 52 in humans (Corden, 2013, Eick and Geyer, 2013, Fisher, 2012, Jasnovidova and Stefl, 2013, Jeronimo et al., 2013, Jeronimo et al., 2016). The CTD is not required for catalytic activity of the polymerase, but instead plays a key role in RNA processing and chromatin organization by acting as a landing pad for regulatory proteins, allowing the coordination of transcriptional and cotranscriptional events (Jeronimo et al., 2013). The consensus heptapeptide can be phosphorylated at Tyr1, Ser2, Thr4, Ser5 and Ser7 and is a target of many kinases and phosphatases and post-translational modifying enzymes (Jeronimo et al., 2016). With greater understanding of the role of the CTD it has become clear that specific and temporal post-translational modifications of the CTD regulate the activity of RNA polymerase II globally, and in a gene-specific manner, in response to environmental stimuli or the cellular state (Bataille et al., 2012, Drogat and Hermand, 2012, Mayer et al., 2010). Studies in yeast have determined a cycle of regulation (Fig. 3). When RNA polymerase II is recruited to promoters it becomes phosphorylated on Ser5 and Ser7 before initiating transcription. Following the initiation of transcription Ser5 phosphorylation decreases while Ser2 and Tyr1 phosphorylation increases. When transcription terminates Tyr1 is the first residue to be dephosphorylated, closely followed by Ser5, Ser7 and Ser2. A similar pattern of CTD phosphorylation occurs in other higher eukaryotes (Fig. 3), although possibly with the exception of the modification of Tyr1 (Corden, 2013, Eick and Geyer, 2013, Jasnovidova and Stefl, 2013, Jeronimo et al., 2013, Jeronimo et al., 2016). The multiple kinases that phosphorylate the CTD have been identified and, of relevance to this review, include CDKs (Jeronimo et al., 2016).