Open AccessStructure Based Design of Potent Selective Inhibitors of Protein Kinase D1 (PKD1)
Author(s) -
Jianwen Feng,
Patrick Lee,
Moulay Hicham Alaoui,
Kathy Barrett,
Georgette Castanedo,
Robert Godemann,
Paul McEwan,
Xiaolu Wang,
Ping Wu,
Yamin Zhang,
S.F. Harris,
Steven T. Staben
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.8b00658
Subject(s) - hydrogen bond , chemistry , propargyl , kinase , stereochemistry , pkd1 , biochemistry , combinatorial chemistry , computational biology , biology , molecule , genetics , catalysis , organic chemistry , polycystic kidney disease , kidney
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.