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A Targeted Library Screen Reveals a New Inhibitor Scaffold for Protein Kinase D

Tandon, M and Wang, L and Xu, Q and Xie, X and Wipf, P and Wang, QJ (2012) A Targeted Library Screen Reveals a New Inhibitor Scaffold for Protein Kinase D. PLoS ONE, 7 (9).

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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 model based on similar protein kinase structures, docking modes for compound 139 were explored and compared to literature examples of PKD inhibition. Modeling of these compounds at the ATP-binding site of PKD was used to rationalize its high potency and provide the foundation for future further optimization. Accordingly, using biochemical screening of a small number of privileged scaffolds and computational modeling, we have identified a new core structure for highly potent PKD inhibition with promising selectivity against closely related kinases. These lead structures represent an excellent starting point for the further optimization and the design of selective and therapeutically effective small molecule inhibitors of PKD. © 2012 Tandon et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Tandon, Mmat137@pitt.eduMAT137
Wang, LLIW30@pitt.eduLIW30
Xu, Q
Xie, XSean.Xie@pitt.eduXIX15
Wipf, Ppwipf@pitt.eduPWIPF
Wang, QJqjw1@pitt.eduQJW1
ContributionContributors NameEmailPitt UsernameORCID
Date: 18 September 2012
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 7
Number: 9
DOI or Unique Handle: 10.1371/journal.pone.0044653
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
School of Medicine > Pharmacology and Chemical Biology
School of Pharmacy > Pharmaceutical Sciences
Refereed: Yes
Other ID: NLM PMC3445516
PubMed Central ID: PMC3445516
PubMed ID: 23028574
Date Deposited: 19 Oct 2012 21:24
Last Modified: 13 Apr 2020 12:55


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