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Joint Research Collaboration Between Novartis, QUB Chemistry, and the QUB CCRCB Provides Important New Insights Into How the A83586C-GE3-Citropeptin Macrolides Function as Anticancer Agents
For many years, mystery has surrounded how the A83586C-GE3-citropeptin family of antitumour natural products are able to function as powerful anticancer agents. A recent collaboration between the Hale-Manaviazar and El-Tanani groups of QUB, and the Novartis Oncology Taskforce, has now given some important new insights into these effects in an important new paper published in Organic Letters. Specifically, the combined team has shown that A83586C is able to serve as a powerful E2F transcription factor inhibitor, and that it can also simultaneously bring about the conversion of tumour-promoting hyper-phosphorylated retinoblastoma protein (pRb) into its dephosphorylated, tumour-suppressing, form without causing pRb degradation.
The team also demonstrated that molecules of the A83586C class are able to switch off transcription from the TCF4 promoter by disrupting the interaction between the TCF4 and b-catenin proteins in human colon cancer cells at IC50 values of between 3 and 5 nM. b-Catenin-driven gene transcription from the TCF4 promoter is frequently upregulated in many cancers, where it switches on the expression of many genes critically involved human cancer cell proliferation and metastasis. In this regard, the combined team demonstrated that A83586C type molecules are able to potently downregulate expression of the important b-catenin/TCF4 target gene, osteopontin (Opn), which is now heavily implicated in the invasion and spread of metastatic tumours when present at elevated levels.
According to Professor Hale: “Our joint work with Novartis and the El-Tanani group in the CCRCB has now proven that it is possible to disrupt the oncogenic b-catenin/TCF4 protein-protein interaction with small molecule drugs and very effectively shut down production of this powerful metastasis-inducing protein. The fact that A83586C-type molecules are also able to concurrently act as E2F transcription factors inhibitors at much higher concentrations is also of great interest since this too is a novel mechanism of antitumour action”. For more details of this work see:
Synthesis of A83586C Analogs with Potent Anticancer and E2F/b-Catenin/ TCF4/Osteopontin Inhibitory Effects and Insights Into How A83586C Modulates E2Fs and pRb
Hale KJ, Manaviazar S, Lazarides L, George J, Walters MA, Cai J, Delisser VM, Bhatia GS, Peak SA, Dalby SM, Lefranc A, Chen Y-NP, Wood A, Crowe P, Erwin P and El-Tanani M Org. Lett. 2009, 11, 737. http://pubs.acs.org/doi/abs/10.1021/ol802818f
