Seliciclib (CYC202, R-roscovitine) is a cyclin-dependent kinase (CDK) inhibitor that competes for the ATP binding site on the kinase. It has greatest activity against CDK2/cyclin E, CDK7/ cyclin H, and CDK9/cyclin T. Seliciclib induces apoptosis from all phases of the cell cycle in tumor cell lines, reduces tumor growth in xenografts in nude mice and is currently in phase II clinical trials. This study investigated the mechanism of cell death in multiple myeloma cells treated with seliciclib. In myeloma cells treated in vitro, seliciclib induced rapid dephosphorylation of the carboxyl-terminal domain of the large subunit of RNA polymerase II. Phosphorylation at these sites is crucial for RNA polymerase II-dependent transcription. Inhibition of transcription would be predicted to exert its greatest effect on gene products where both mRNA and protein have short half-lives, resulting in rapid decline of the protein levels. One such gene product is the antiapoptotic factor Mcl-1, crucial for the survival of a range of cell types including multiple myeloma. As hypothesized, following the inhibition of RNA polymerase II phosphorylation, seliciclib caused rapid Mcl-1 down-regulation, which preceded the induction of apoptosis. The importance of Mcl-1 was confirmed by short interfering RNA, demonstrating that reducing Mcl-1 levels alone was sufficient to induce apoptosis. These results suggest that seliciclib causes myeloma cell death by disrupting the balance between cell survival and apoptosis through the inhibition of transcription and down-regulation of Mcl-1. This study provides the scientific rationale for the clinical development of seliciclib for the treatment of multiple myeloma. (Cancer Res 2005; 65(12): 5399-407)

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Parkinson’s is the second most common neurodegenerative disease, with the number of individuals susceptible due to increase as a result of increasing life expectancy and a growing worldwide population. However, despite the number of individuals affected, all current treatments for PD are symptomatic—they alleviate symptoms, but do not slow disease progression. A major reason for the lack of disease-modifying treatments is that there are currently no methods to diagnose individuals during the earliest stages of the disease, nor are there any methods to monitor disease progression at a biochemical level. Herein, we have designed and evaluated a peptide-based probe to monitor αS aggregation, with a particular focus on the earliest stages of the aggregation process and the formation of oligomers. We have identified the peptide-probe K1 as being suitable for further development to be applied to number of applications including: inhibition of αS aggregation; as a probe to monitor αS aggregation, particularly at the earliest stages before Thioflavin-T is active; and a method to detect early-oligomers. With further development and in vivo validation, we anticipate this probe could be used for the early diagnosis of PD, a method to evaluate the effectiveness of potential therapeutics, and as a tool to help in the understanding of the onset and development of PD.