Article

3,5-Disubstituted-indole-7-carboxamides: The discovery of a novel series of potent, selective inhibitors of IKK-β

GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
Bioorganic & medicinal chemistry letters (Impact Factor: 2.33). 03/2011; 21(8):2255-8. DOI: 10.1016/j.bmcl.2011.02.107
Source: PubMed

ABSTRACT The discovery and hit-to-lead exploration of a novel series of selective IKK-β kinase inhibitors is described. The initial lead fragment 3 was identified by pharmacophore-directed virtual screening. Homology model-driven SAR exploration of the template led to potent inhibitors, such as 12, which demonstrate efficacy in cellular assays and possess encouraging developability profiles.

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    ABSTRACT: The transcription factors NF-κB and IFN control important signaling cascades and mediate the expression of a number of important pro-inflammatory cytokines, adhesion molecules, growth factors and anti-apoptotic survival proteins. IκB kinase (IKK) and IKK-related kinases (IKKe and TBK1) are key regulators of these biological pathways and, as such, modulators of these enzymes may be useful in the treatment of inflammatory diseases and cancer. We have reviewed the most recent IKK patent literature (2008–2012), added publications of interest overlooked in previous patent reviews and identified all the players involved in small-molecule inhibitors of the IKKs. This will provide the reader with a decisive summary of the IKK arena, a field that has reached maturity over a decade of research. The inhibitory κB kinase (IKK) family consists of four isoforms: IKKa (or IKK1), IKKb (or IKK2), IKKe (or IKKi) and TRAF-associated NF-κB activator (TANK)-binding kinase 1 (TBK1). Each one contains 730–756 residues with an N-terminal kinase domain of approximately 300 residues followed by a C-terminal leucine zipper and a helix-loop-helix motif [1]. The crystal structure of the IKKb isoform has recently been solved, revealing that the leucine zipper and helix-loop-helix domains are part of an a-helical scaffold/dimerization domain, which medi-ates IKKb dimerization [2]. IKKa and IKKb share 51% amino acid identity [3] and their role in the activation of the NF-κB pathway has been investigated extensively [4]. NF-κB is a family of transcription factors that regulates gene expression in-volved in cell growth, inflammation and immunity [5], and hyperactivation of the pathway has been linked to diseases such as inflammatory disorders and cancer [6,7]. In mammals, NF-κB has five member proteins: p65 (or RelA), p50 (or NF-κB1), p52 (or NF-κB2), RelB and c-Rel, which reside in the cytoplasm as inactive homo-or hetero-dimers sequestrated by a member of the inhibitory κB (IκB) pro-teins [8,9] and can be activated through the canonical (classical) and the noncanoni-cal (alternative) pathway [10,11]. The canonical pathway is activated through a vari-ety of stimulants such as TNF-a, IL-1, viruses and genotoxic agents, which induce phosphorylation of the IKK complex, which is formed by IKKa, IKKb and the small scaffolding and regulatory subunit NEMO [12,13]. The activated IKK complex phosphorylates the IκBa protein, which is then ubiquinated and degraded by the proteasome and liberates the NF-κB p50:p65 dimer to enable nuclear translocation and initiate gene expression [13]. Whereas the canonical pathway is predominantly dependent on NEMO and IKKb [12], the noncanonical pathway is reliant upon IKKa [14]. This cascade is activated by TNF receptor members, such as B cell-activating factor, receptor activator of NF-κB, CD40 ligand, lymphotoxin-b recep-tors and TNF-related weak inducer of apoptosis all of which induce degradation of TRAF3 (TNF receptor-associated factor) [15]. In non-activated cells, TRAF3 maintains low levels of NIK (NF-κB inducing kinase), therefore when TRAF3 is
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