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The nuclear transcription factor NF-κB has a crucial role in the pathogenesis of several human disorders, particularly those with an inflammatory component. Because the multisubunit IκB kinase (IKK) is vital for translating pro-inflammatory stimuli into the activation of NF-κB, this kinase provides an opportunity to develop novel therapeutics. In this article, we review the investigations, both genetic and pharmacological, that demonstrate the use of IKK inhibition in autoimmune and inflammatory disorders. It is still unclear what toxicities will be associated with IKK inhibitors; a discussion of the potential for mechanism-based toxicities such as teratogenicity, lymphopoietic defects and susceptibility to infection is also presented. [Copyright &y& Elsevier]

[Display omitted] Efforts directed at improving potency and preparing structurally different TYK2 JH2 inhibitors from the first generation of compounds such as 1a led to the SAR study of new central pyridyl based analogs 2 – 4. The current SAR study resulted in the identification of 4h as a potent and selective TYK2 JH2 inhibitor with distinct structural differences from 1a. In this manuscript, the in vitro and in vivo profiles of 4h are described. The hWB IC 50 of 4h was shown as 41 nM with 94% bioavailability in the mouse PK study. [ABSTRACT FROM AUTHOR]

Abstract: Investigation of various heterocyclic core isosteres of imidazopyrazines 1 &2 yielded purine derivatives 3 &8 as potent and selective BTK inhibitors. Subsequent SAR studies of the purine series led to the discovery of 20 as a leading compound. Compound 20 is very selective when screened against a panel of 400 kinases and is a potent inhibitor in cellular assays of human B cell function including B-Cell proliferation and CD86 cell surface expression and exhibited in vivo efficacy in a mouse PCA model. Its X-ray co-crystal structure with BTK shows that the high selectivity is gained from filling a BTK specific lipophilic pocket. However, physical and ADME properties leading to low oral exposure hindered further development. [Copyright &y& Elsevier]

Studies the role of signal-inducible phosphorylation of serines 32 and 36 of I-kappa-B-alpha in regulating the subsequent ubiquitination and proteolysis of I-kappa-B-alpha. Promotion of gene transcription; Non-linear relationship indicating non-Michaelis-Menten kinetic binding; Study of NF-kappa B activation.