The Renaissance of Cyclin Dependent Kinase Inhibitors

Abstract

Cyclin-dependent kinases (CDK) regulate cell cycle progression. During tumor development, altered expression and availability of CDKs strongly contribute to impaired cell proliferation, a hallmark of cancer. In recent years, targeted inhibition of CDKs has shown considerable therapeutic benefit in a variety of tumor entities. Their success is reflected in clinical approvals of specific CDK4/6 inhibitors for breast cancer. This review provides a detailed insight into the molecular mechanisms of CDKs as well as a general overview of CDK inhibition. It also summarizes the latest research approaches and current advances in the treatment of head and neck cancer with CDK inhibitors. Instead of monotherapies, combination therapies with CDK inhibitors may especially provide promising results in tumor therapy. Indeed, recent studies have shown a synergistic effect of CDK inhibition together with chemo- and radio- and immunotherapy in cancer treatment to overcome tumor evasion, which may lead to a renaissance of CDK inhibitors.

Keywords: CDK; CDK4/CDK6; CDKI; HNSCC; PD-L1; abemaciclib; cell cycle inhibition/blockade; chemosensitization; flavopiridol; immunosensitization; palbociclib; radiosensitization; ribociclib; seliciclib; synergy; trilaciclib.

Figure 1

pRb proteins bind to and block E2F transcription factors, controlling the expression of E2F responsive genes in specific cell cycle phases. After being hyperphosphorylated at the restriction point (R-point), pRb proteins release E2F transcription factors allowing them to activate the transcription of numerous genes crucial for cell cycle progression. When cells enter S phase, E2Fs are degraded. Hence, E2Fs are active only from late G1 until entry into S phase.

Figure 2

Pairing of cyclins with the respective CDK during cell cycle progression. Mitogenic stimulation leads to the synthesis of D-type cyclins via mitogenic pathways, activating CDK4/CDK6/cyclin D and ultimately CDK2/cyclin E. CDK4/CDK6 phosphorylate Rb proteins (dotted lines) and CDK2 further phosphorylates Rb subsequently reversing suppression of transcription factor E2F1. This allows DNA synthesis to occur. S phase is terminated when CDK2/cyclin A phosphorylates E2F1, blocking its DNA-binding ability. CDK7, CDK8/CDK19, CDK9 CDK11 and CDK12/CDK13 are all involved in transcriptional initiation and DNA elongation processes.

Figure 3

Basic scheme of the sequential action of different cyclin/CDK complexes which are important for the phosphorylation cycle and consequently the activity of RNA polymerase II (RNA Pol II). Accordingly, inhibitors against these CDKs interfere with the RNA transcription process (modified according to Parua et al. [14]).

Figure 4

Cell intrinsic CDKCDKIs block the actions of CDKs at various time points of the cell cycle. The four illustrated INK proteins specifically inhibit cyclin D/CDK4/CDK6 complexes which are active in the G1 phase of the cell cycle. The three illustrated Cip/Kip proteins inhibit the remaining cyclin/CDK complexes which are active throughout the whole cell cycle.

Figure 5

Schematic representation of stapled peptides. To keep the peptide into a more stable alpha helical form and optimize its properties, individual amino acids are crosslinked together. Stapled peptides can enter cells, bind to therapeutic targets and modulate biological structures and properties, and may be of great interest as inhibitors of protein-protein interactions (PPI).

Figure 6

Schematic representation illustrating the mode of action of proteolysis targeting chimeras (PROTACs) and molecular glues. Chemical compounds that bind to both target protein and ubiquitinylating E3 ligase to bring these proteins into spatial proximity. The target protein is then tagged and proteasomally degraded.

Figure 7

Structure of the first-generation pan-CDK inhibitors flavopiridol (also known as alvocidib) and roscovitine (also known as seliciclib).

Figure 8

Structure of the second-generation pan-CDK inhibitors dinaciclib (also known as MK-7965 or SCH7279656) and AT7519.

Figure 9

Structure of CDK1 inhibitors RO3306 and sorafenib.

Figure 10

Structure of CDK2 inhibitor HI 5.

Figure 11

Structure of the specific CDK4/6 inhibitors palbociclib (also known as PD 0332991), ribociclib (also known as LEE011) and abemaciclib (also known as LY2835219).

Figure 12

Structure of the novel specific CDK4/6 inhibitor trilaciclib.

Figure 13

Structure of CDK7 inhibitors LDC3140, LDC4297, THZ1 and THZ2.

Figure 14

Structure of the specific CDK7 inhibitor SY-5609.

Figure 15

Structure of CDK8/19 inhibitors cortistatin A, CCT251545, CCT251921 and MSC2530818.

Figure 16

Structure of CDK9 inhibitors CDKI-71, CDKI-73 and LDC000067.

Figure 17

Structure of the specific CDK9 inhibitor AZD4573.

Figure 18

Structure of CDK12/13 inhibitors SR-4835 and THZ2531.

Figure 19

Sensitization to immunotherapy by CDKIs. CDK inhibition prevents cell cycle progression and triggers an IFNγ response accompanied by MHC I/II upregulation. CDK inhibition also leads to stabilization of PD-L1 membrane expression of tumor cells. The additional use of immune checkpoint inhibitors, such nivolumab and pembrolizumab, blocks the interaction between the inhibitory checkpoint PD-1 and its ligand PD-L1. This prevents resistance to the immune response. As a result, cytotoxic T cells proliferate, leading to efficient tumor cell killing and clinical response.