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CDK INHIBITORS IN REGULATING CELL CYCLE

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.

References

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