Structure Based Design of Potent Selective Inhibitors of Protein Kinase D1 (PKD1).
Basic Information
ID: ALA4304809
Journal: ACS Med Chem Lett
Title: Structure Based Design of Potent Selective Inhibitors of Protein Kinase D1 (PKD1).
Authors: Feng JA, Lee P, Alaoui MH, Barrett K, Castanedo G, Godemann R, McEwan P, Wang X, Wu P, Zhang Y, Harris SF, Staben ST.
Abstract: We previously disclosed a series of type I 1/2 inhibitors of NF-κB inducing kinase (NIK). Inhibition of NIK by these compounds was found to be strongly dependent on the inclusion and absolute stereochemistry of a propargyl tertiary alcohol as it forms critical hydrogen bonds (H-bonds) with NIK. We report that inhibition of protein kinase D1 (PKD1) by this class of compounds is not dependent on H-bond interactions of this tertiary alcohol. This feature was leveraged in the design of highly selective inhibitors of PKD1 that no longer inhibit NIK. A structure-based hypothesis based on the position and flexibility of the α-C-helix of PKD1 vs NIK is presented.
CiteXplore: 31531194
DOI: 10.1021/acsmedchemlett.8b00658
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