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Cyclin-dependent kinases Cdk4 and Cdk6: targets for cancer treatment and visualization.

Graf, F.; Köhler, L.; Mosch, B.; Steinbach, J.; Pietzsch, J.

Abstract

Cancerogenesis is closely associated with deregulated cell proliferation and, consequently, aberrant cell cycle control. The first phase of the cell cycle (G1) comprises important steps for initiation of DNA replication and subsequent cell division. The activation and coordination of G1 phase is accomplished by enzymes of serine/threonine kinase family. As members of this protein family and important regulators of early cell cycle machinery, cyclin-dependent kinases 4 and 6 (Cdk4/6) associate with regulatory protein cyclin D, and phosphorylate retinoblastoma protein pRb. Hyperphosphorylated pRb dissociates from E2F transcription factors and triggers transcription of genes required for further G1 phase progression. Hence, Cdk4/6 were identified as essential and critical activators of G1 phase in human embryogenesis, homeostasis, and cancer development; G1 phase progression in cell cycle by phosphorylation of retinoblastoma protein pRb and thua, activation of gene transcription.
In 80% of human tumors the Cdk4/6-cyclin D/ pRb/ E2F pathway is altered provoked by multiple mechanisms. In tumor formation, hyperactivation of Cdk4/6 is often a result of overexpression, silencing, and epigenetic alteration of their regulators or substrates. On the other hand, disruption of Cdk4/6-associated cell cycle control in cancer is also caused directly by mutations and amplification of Cdk4/6 themself. Cdk4/6 protein amplification was found in a wide spectrum of solid tumors and blood cell cancer, e.g., gliomas, lymphomas, melanomas, carcinomas, and leukemias. In consequence, Cdk4/6 were considered to be attractive targets for pharmacological anti-cancer drug development. In the recent years, Cdk4/6 inhibitors of high potency and selectivity against other kinases, especially other cyclin-dependent kinases, were developed and evaluated. One of these compounds, a pyrido[2,3-d]pyrimidine-7-one derivative currently is undergoing clinical trials for cancer therapy.
Though, potent and selective pyrido[2,3-d]pyrimidine-7-one Cdk4/6 inhibitors are not only promising new compounds for cancer therapy, but also for visualization and functional characterization of human tumors. Radiolabeled Cdk4/6 inhibitors could be of particular interest for the assessment of Cdk4/6 protein status and Cdk4/6 activity of human tumors by non-invasive imaging technique positron-emission-tomography (PET). PET affords the opportunity of three-dimensional imaging of physiological processes in vivo. Additionally, PET would provide pharmacological data of radiolabeled Cdk4/6 inhibitors, which may help to estimate the applicability of the compounds for tumor therapy. In this regard, positron-emitting Cdk4/6 inhibitors were designed, synthesized and characterized in our institute for the first time. The radiolabeled compounds and their nonradioactive analogs are based on the lead structure of pyrido[2,3-d]pyrimidine-7-one CKIA.
First, iodine-containing pyrido[2,3-d]pyrimidine-7-one derivatives CKIA and CKIB were evaluated concerning their efficacy and suitability as Cdk4/6 inhibitors in human tumor cell lines. The compounds showed both significant and specific inhibition of tumor cell proliferation and G1 phase arrest by targeting the Cdk4/6-cyclin D/ pRb/ E2F signaling pathway [2]. The iodine substituent of CKIA and CKIB represents an attractive site for an isotopic substitution with the positron emitter iodine-124 (124I). 124I-labeled Cdk4/6 inhibitors [124I]CKIA and [124I]CKIB were evaluated concerning their radiopharmacological properties in cellular radiotracer uptake studies, biodistribution studies, and small animal PET studies in NMRI nu/nu mice bearing the human squamous cell carcinoma tumor FaDu [3]. With 4.18 d half-life, 124I affords extended radiopharmacological evaluation and imaging studies using PET. Nevertheless, high positron energy and minor positron emission (26%) are disadvantages, especially for the resolution of PET images. ....

  • OncoPost & OncoPeople The official Newspaper of the ECCO 15 – 34th ESMO Congress 3(2009), 10

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