| Summary: | The transcription factor NF-κB (Nuclear Factor kappa B) mediates the expression of a number of pro-inflammatory cytokines, adhesion molecules, growth factors, and anti-apoptosis survival proteins. NF-κB transcriptional activity is normally suppressed in the cytosol via complexation with its natural inhibitor molecule IκB. Various cellular stress and pro-inflammatory stimuli can result in the translocation and hence activation of NF-κB into the nucleus via the degradation of IκB. The proteolytic destruction of IκB via the ubiquitin-proteasome pathway is triggered by phosphorylation of IκB at Ser32 and Ser36 by the IκB kinase complex (IKK). As such, inhibitors of IKK may be useful in the treatment of cancer as well as in inflammatory diseases. In particular, prostate cancer has been linked with misregulation of the NF-κB pathway and the IKK subunit 1 (IKK1). As part of a multidisciplinary project targeting hormone refractory prostate cancer, a collection of small molecules was screened against IKK1 and revealed Nucleoside Q Precursor as a moderate inhibitor of IKK1. The development of a robust synthetic route for 4-aminopyrrolopyrimidines allowed access to a diversity of derivatives of this initial hit and highlighted three classes of active substituents: aminoethanol, cyclohexylamine and cyclic tertiary amine derivatives. Further derivatization of these compounds allowed us to develop a sub-micromolar and some single-digit micromolar inhibitors of IKK1 with up to 30-fold selectivity over IKK2. The most potent inhibitors were rare nucleoside-like structures containing a complex carbocyclic moiety at the 4-position of a pyrrolopyrimidine ring. These active compounds have been inspired by the natural product IKK1 inhibitor Noraristeromycin, and prepared following an asymmetric synthesis with excellent levels of diastereoselectivity. Furthermore, a series of 3-aminoindazoles have been identified as IKK1 inhibitors. These compounds showed sub-micromolar IKK1 inhibition levels and up to 100-fold selectivity over IKK2. These exciting preliminary results have encouraged us to focus on this new scaffold and the development of this promising class of compounds is currently ongoing.
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