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

ABSTRACT: We previously disclosed a series of type I 1/2 inhibitors of NF-?B 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 ?-C-helix of PKD1 vs NIK is presented.

SUBMITTER: Feng JA

PROVIDER: S-EPMC6746091 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Feng Jianwen A JA Lee Patrick P Alaoui Moulay Hicham MH Barrett Kathy K Castanedo Georgette G Godemann Robert R McEwan Paul P Wang Xiaolu X Wu Ping P Zhang Yamin Y Harris Seth F SF Staben Steven T ST

ACS medicinal chemistry letters 20190724 9

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 select ...[more]

PMID: 31531194

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