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Structure based design of potent selective inhibitors of protein kinase D1 (PKD1)

DOI: 10.1021/acsmedchemlett.8b00658 DOI Help

Authors: Jianwen A. Feng (Genentech) , Patrick Lee (Genentech) , Moulay Hicham Alaoui (Genentech) , Kathy Barrett (Genentech) , Georgette M. Castanedo (Genentech) , Robert Godemann (Evotec AG) , Paul A. Mcewan (Evotec (UK) Ltd) , Xiaolu Wang (Evotec AG) , Ping Wu (Genentech) , Yamin Zhang (Pharmaron Beijing Co., Ltd) , Seth F. Harris (Genentech) , Steven T Staben (Genentech)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acs Medicinal Chemistry Letters

State: Published (Approved)
Published: July 2019

Abstract: We previously disclosed a series of type I ½ 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.

Journal Keywords: Structure-based drug design; kinase inhibitor; PKD1 (protein kinase D1); NIK (NF-κB inducing kinase)

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Other Facilities: Stanford Synchrotron Radiation Light Source