As part of a multidisciplinary project targeting hormone refractory prostate cancer, a collection of small molecules were screened against IKK and NF-kB. Initial screening revealed a purine-like scaffold as a moderate inhibitor of IKK. Derivatization of this initial hit allowed us to develop a single-digit micromolar inhibitor of IKK, with a 30-fold selectivity of one isoform over the other and good P450 metabolism profile. In order to understand the structure activity relationship (SAR), we built a homology model using Accelrys Discovery Studio software. This hypothetical 3D model, guided us through the design of new chiral amine ligands for our scaffold in order to increase potency and control selectivity.Here we would like to present the asymmetric synthesis of enantiopure cis-3 and trans-3-arylcyclohexylamines, 3-aminocyclopentane-1,2-diols and 4-aminocyclopentane-1,2,3-triols as ligands for our IKK inhibitor scaffold.

Design and synthesis of novel and selective IKK inhibitors

241st National Meeting (2011)

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