The S/T kinase CDK9 is part of the P-TEFb complex which promotes the productive transcriptional elongation via phosphorylation of serine-2 residues within the RNA polymerase II C-terminal repeat domain. P-TEFb, recruited to responsive promoters via binding to transcription factors or chromatin associated proteins (e.g. NF-kB), is specifically required for the expression of highly inducible genes controlled by extracellular stimuli such as inflammatory processes. Consequently, the selective inhibition of CDK9 leads to a reduced expression of pro-inflammatory mediators, thereby avoiding the interference with processes of the normal cell homeostasis.Selective CDK9 inhibitors, resulting from our lead development program, have shown to be effective in various acute as well as chronic inflammation models, thereby confirming the proposed mode of action. The lead optimization process resulted in a CDK9 inhibitor, effective and well tolerated in two mouse models of arthritis under prophylactic as well as therapeutic treatment, now entering drug the development phase.

CDK9-selective kinase inhibitors as a treatment of inflammatory diseases

243rd National Meeting (2012)

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