Introduction: Cyclin dependent Kinases

In total 512 human versions serine/therione/tyrosine kinases have been discovered leading to the theoretical formation of multiple pathways that govern all aspects of cellular life and death. Research has confirmed many of these controls but aspects of these mechanisms still remain controversial. One of earliest kinase pathways to be discovered was the Cyclin dependant kinases [1]. These kinases were shown to be a major regulatory mechanism of the cell cycle growth patterns, apoptotic processes, pain, gene transcription, and RNA formation [2]. Mechanisms with which CDK action and response is controlled can be by phosphorylation or degradation, natural inhibitory proteins [3;4], movement of the kinase around the cell or nucleus [5;6] and by formation complexes with other regulatory proteins [7]. Natural inhibitors include p16 (Ink4) [8-10], p21 (CIP1) [11-14] and p27 (KIP1/2) [15] all of which have been demonstrated to be mutated in numerous cancer tumor types [16;17]. CDK’s have been shown to regulate G1 phase and S in the cell cycle [18;19]. There are at least 9 CDK’s found in mammalian cells with 1-4 directly involved in cell cycle progress. CDK’s operate by complexing with cyclin ligands to form a regulatory complex. CDK1 has been shown to complex with cyclin B and controls aspects of the M-phase. CDK2 form complexes with cyclin E or A and are involved in the G1/S phase transition or the S-G2 phase transition [20]. CDK3 form complexes with cyclin C and has be theorized to be in the regulation sequence of the G1 phase. CDK4 forms complexes with cyclin D and again is linked with the G1 phase regulation [21;22]. In transcription processes multiple complexes have been discovered which dictate how genes are transcribed, CDK5 forms complexes with p53 which is a regulatory complex of transcription [23]. The extraordinary number of complexes and there variety demonstrates the sheer complexity of the protein kinase pathways [23]. CDK’s have also been linked to the developmental processes of neuron formation and their signaling processes, this has even been linked to a possible cause of drug addiction/abuse [24]. With the roles of CDK’s being established the focus has shifted from mechanisms to inhibition. With most tumors being linked to uncontrolled cellular growth, CDK inhibition was assumed to be a potential solution. However, the sheer complexity of inhibiting a regulatory protein of this type and predicting outcome is proving very difficult. Development of CDK inhibitor drugs has progressed to clinical trials, examples of molecules which have shown CDK inhibition properties Thio/oxoflavopiridols, Oxindoles, Aminothiazoles, Benzocarbazoles and Pyrimidines [25-27].

CDK Inhibitors: Clinical Status

Examples of CDK kinase inhibitors currently in clinical testing phase include the CDK antagonist Alvocidib, which is also known as flavopiridol, has been found to be a pan-Cdk inhibitor (1,2&4). Preclinical testing has demonstrated that in murine xenografts with colorectal cells Alvocidib demonstrate cell growth inhibition [28]. Research is at an early stage and progressing in acute myeloid leukemia, hairy cell leukemia, neuroblastoma and colorectal cancer (in combination with FOLFIRI). Another CDK selective inhibitor under clinical development is Seliciclib which is substituted purine analog. Research has demonstrated that it is a potent CDK-2 inhibitor with lesser activity against CDK 7 & 9 as well. It has demonstrated anti-tumor activity and anti-viral activity as well. Amazingly Seliciclib has been shown to kill cells possessing the HIV virus, suggesting a means treating this 21st centaury plague [29-32]. Currently Seliciclib is a CDK inhibitor in clinical trials treating NSCLC as a combined treatment with traditional first line therapy, it is also under investigation as sole therapy for NSCLC patients showing resistance to fisrt and second line traditional therapy. Unfortunately Seliciclib, while showing positive tumor response, is demonstrating detrimental toxicity [33]. Other less developed CDK specific inhibitors include Olomoucine, Roscovitine, Purvalanol, Paullones and Butryolactone. Reseachers can buy CDK inhibitors from most cell biological suppliers at a reasonable cost.


    1.    Evans T, Rosenthal ET et al. Cyclin: a protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division. Cell 1983; 33(2):389-396.

    2.    Gitig DM, Koff A. Cdk pathway: cyclin-dependent kinases and cyclin-dependent kinase inhibitors. Methods Mol Biol 2000; 142:109-123.

    3.    Prosperi E. Multiple roles of the proliferating cell nuclear antigen: DNA replication, repair and cell cycle control. Prog Cell Cycle Res 1997; 3:193-210.

    4.    Lu Z, Hunter T. Ubiquitylation and proteasomal degradation of the p21(Cip1), p27(Kip1) and p57(Kip2) CDK inhibitors. Cell Cycle 2010; 9(12):2342-2352.

    5.    van den Heuvel S. Cell-cycle regulation. WormBook 2005;1-16.

    6.    Tannoch VJ, Hinds PW et al. Cell cycle control. Adv Exp Med Biol 2000; 465:127-140.

    7.    Nebreda AR. CDK activation by non-cyclin proteins. Curr Opin Cell Biol 2006; 18(2):192-198.

    8.    Ohtani N, Yamakoshi K et al. The p16INK4a-RB pathway: molecular link between cellular senescence and tumor suppression. J Med Invest 2004; 51(3-4):146-153.

    9.    Bartkova J, Rajpert-De ME et al. Deregulation of the G1/S-phase control in human testicular germ cell tumours. APMIS 2003; 111(1):252-265.

  10.    Satyamoorthy K, Herlyn M. p16INK4A and familial melanoma. Methods Mol Biol 2003; 222:185-195.

  11.    Abukhdeir AM, Park BH. P21 and p27: roles in carcinogenesis and drug resistance. Expert Rev Mol Med 2008; 10:e19.

  12.    Ball KL. p21: structure and functions associated with cyclin-CDK binding. Prog Cell Cycle Res 1997; 3:125-134.

  13.    Child ES, Mann DJ. The intricacies of p21 phosphorylation: protein/protein interactions, subcellular localization and stability. Cell Cycle 2006; 5(12):1313-1319.

  14.    Coqueret O. New roles for p21 and p27 cell-cycle inhibitors: a function for each cell compartment? Trends Cell Biol 2003; 13(2):65-70.

  15.    Borriello A, Bencivenga D et al. Targeting p27Kip1 protein: its relevance in the therapy of human cancer. Expert Opin Ther Targets 2011; 15(6):677-693.

  16.    Novotny L, Szekeres T. Cancer therapy: new targets for chemotherapy. Hematology 2003; 8(3):129-137.

  17.    Johansson M, Persson JL. Cancer therapy: targeting cell cycle regulators. Anticancer Agents Med Chem 2008; 8(7):723-731.

  18.    Hengstschlager M, Braun K et al. Cyclin-dependent kinases at the G1-S transition of the mammalian cell cycle. Mutat Res 1999; 436(1):1-9.

  19.    Teer JK, Dutta A. Regulation of S phase. Results Probl Cell Differ 2006; 42:31-63.

  20.    Jackman MR, Pines JN. Cyclins and the G2/M transition. Cancer Surv 1997; 29:47-73.

  21.    Lee MH, Yang HY. Regulators of G1 cyclin-dependent kinases and cancers. Cancer Metastasis Rev 2003; 22(4):435-449.

  22.    Liu N, Fang H et al. Recent research in selective cyclin-dependent kinase 4 inhibitors for anti-cancer treatment. Curr Med Chem 2009; 16(36):4869-4888.

  23.    Loyer P, Trembley JH et al. Role of CDK/cyclin complexes in transcription and RNA splicing. Cell Signal 2005; 17(9):1033-1051.

  24.    Bibb JA. Role of Cdk5 in neuronal signaling, plasticity, and drug abuse. Neurosignals 2003; 12(4-5):191-199.

  25.    Garrett MD, Fattaey A. CDK inhibition and cancer therapy. Curr Opin Genet Dev 1999; 9(1):104-111.

  26.    Fischer PM, Gianella-Borradori A. CDK inhibitors in clinical development for the treatment of cancer. Expert Opin Investig Drugs 2003; 12(6):955-970.

  27.    Schang LM, Coccaro E et al. Cdk inhibitory nucleoside analogs prevent transcription from viral genomes. Nucleosides Nucleotides Nucleic Acids 2005; 24(5-7):829-837.

  28.    Darpolor MM, Kennealey PT et al. Preclinical study of treatment response in HCT-116 cells and xenografts with (1) H-decoupled (31) P MRS. NMR Biomed 2011; 24(9):1159-1168.

  29.    Agbottah E, de La FC et al. Antiviral activity of CYC202 in HIV-1-infected cells. J Biol Chem 2005; 280(4):3029-3042.

  30.    Biglione S, Byers SA et al. Inhibition of HIV-1 replication by P-TEFb inhibitors DRB, seliciclib and flavopiridol correlates with release of free P-TEFb from the large, inactive form of the complex. Retrovirology 2007; 4:47.

  31.    Guendel I, Agbottah ET et al. Inhibition of human immunodeficiency virus type-1 by cdk inhibitors. AIDS Res Ther 2010; 7(1):7.

  32.    Nelson PJ, Gelman IH et al. Suppression of HIV-1 expression by inhibitors of cyclin-dependent kinases promotes differentiation of infected podocytes. J Am Soc Nephrol 2001; 12(12):2827-2831.

  33.    Aldoss IT, Tashi T et al. Seliciclib in malignancies. Expert Opin Investig Drugs 2009; 18(12):1957-1965.