Exploiting the p53 pathway to achieve cure in chronic myelogenous leukemia
S. Lain, PhD, Associated Professor
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
In 2008 we reported the discovery and antitumor activity of a small molecule named tenovin-6. In addition, we showed that this compound activates the tumour suppressor p53 as well as inhibits the protein deacetylase activity of sirtuin SirT1. In 2012, a series of remarkable studies were published showing that tenovin-6 increases apoptosis in Chronic Myelogenous Leukemia (CML) stem cells and reduces their growth in vitro and in vivo in combination with imatinib. These exciting preclinical results have encouraged us to synthesize new tenovin-6 analogues and investigate their activity in cells and biochemical assays. Here I will present new findings obtained with our current collection of tenovin analogues and suggest which of these features may influence therapeutic activity. I will also discuss our progress in the identification and mechanism of new compounds for testing in leukemia preclinical models and patient samples.
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