Kinases that are dysregulated in cancer have proven highly effective targets towards the treatment of this disease through the focused blockade of key signaling pathways with small-molecules. However, the efficacy of kinase-selective inhibitors has not met with the expected promise, likely owing to the compensatory upregulation of other signaling pathways. Similarly, the bromodomain epigenetic reader proteins are also involved in tumorigenesis. Bromodomains (BRDs) are protein modules that recognize acetylated lysines of histones, and are involved in transcriptional control. BETs control the expression of genes that are essential for tumor growth, such as c-Myc, and survival, such as Mcl-1.Acute myeloid leukemia (AML) is driven by FLT3 receptor tyrosine kinase and BRD4. The dual inhibition of kinases and bromodomains might, therefore, afford an especially potent treatment for cancers such as AML. It has recently been demonstrated that certain potent kinase inhibitors are also potent bromodomain inhibitors, for example BI-2536 and TG-101348. Herein we describe our efforts towards the optimization of the dual kinase-bromodomain inhibitor BI-2536 as a potential treatment for AML.

Towards dual kinase-bromodomain inhibitors for the treatment of acute myeloid leukemia (AML)

248th National Meeting (2014)

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