Structure Based Design of Potent Selective Inhibitors of Protein Kinase D1 (PKD1)

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 r...

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Veröffentlicht in:	ACS medicinal chemistry letters 2019-09, Vol.10 (9), p.1260-1265
Hauptverfasser:	Feng, Jianwen A, Lee, Patrick, Alaoui, Moulay Hicham, Barrett, Kathy, Castanedo, Georgette, Godemann, Robert, McEwan, Paul, Wang, Xiaolu, Wu, Ping, Zhang, Yamin, Harris, Seth F, Staben, Steven T
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container_title	ACS medicinal chemistry letters
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creator	Feng, Jianwen A Lee, Patrick Alaoui, Moulay Hicham Barrett, Kathy Castanedo, Georgette Godemann, Robert McEwan, Paul Wang, Xiaolu Wu, Ping Zhang, Yamin Harris, Seth F Staben, Steven T
description	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.
doi_str_mv	10.1021/acsmedchemlett.8b00658
format	Article
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Chem. Lett</addtitle><date>2019-09-12</date><risdate>2019</risdate><volume>10</volume><issue>9</issue><spage>1260</spage><epage>1265</epage><pages>1260-1265</pages><issn>1948-5875</issn><eissn>1948-5875</eissn><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. 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title	Structure Based Design of Potent Selective Inhibitors of Protein Kinase D1 (PKD1)
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