原创力文档a targeted library screen reveals a new inhibitor scaffold for protein kinase d针对图书馆屏幕显示一个新的蛋白激酶抑制剂脚手架d.pdfVIP
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a targeted library screen reveals a new inhibitor scaffold for protein kinase d针对图书馆屏幕显示一个新的蛋白激酶抑制剂脚手架d
A Targeted Library Screen Reveals a New Inhibitor
Scaffold for Protein Kinase D
1. 3. 3 3 2,3 1
Manuj Tandon , Lirong Wang , Qi Xu , Xiangqun Xie , Peter Wipf *, Qiming Jane Wang *
1 Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America, 2 Department of Chemistry and Center
for Chemical Methodologies and Library Development, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America, 3 Department of Pharmaceutical
Sciences, University of Pittsburgh, Pittsburgh, Pennsylavania, United States of America
Abstract
Protein kinase D (PKD) has emerged as a potential therapeutic target in multiple pathological conditions, including cancer
and heart diseases. Potent and selective small molecule inhibitors of PKD are valuable for dissecting PKD-mediated cellular
signaling pathways and for therapeutic application. In this study, we evaluated a targeted library of 235 small organic kinase
inhibitors for PKD1 inhibitory activity at a single concentration. Twenty-eight PKD inhibitory chemotypes were identified
and six exhibited excellent PKD1 selectivity. Five of the six lead structures share a common scaffold, with compound 139
being the most potent and selective for PKD vs PKC and CAMK. Compound 139 was an ATP-competitive PKD1 inhibitor with
a low double-digit nanomolar potency and was also cell-active. Kinase profiling analysis identified this class of small
molecules as pan-PKD inhibitors, confirmed their selectivity again PKC and CAMK, and demonstrated an overall favorable
selectivity profile that could be further enhanced through structural modification. Furthermore, using a PKD homology
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