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Discovery of diverse small molecule chemotypes with cell-based PKD1 inhibitory activity

Sharlow, ER and Wilson, GM and Close, D and Leimgruber, S and Tandon, M and Reed, RB and Shun, TY and Wang, QJ and Wipf, P and Lazo, JS (2011) Discovery of diverse small molecule chemotypes with cell-based PKD1 inhibitory activity. PLoS ONE, 6 (10).

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Protein kinase D (PKD) is a novel family of serine/threonine kinases regulated by diacylglycerol, which is involved in multiple cellular processes and various pathological conditions. The limited number of cell-active, selective inhibitors has historically restricted biochemical and pharmacological studies of PKD. We now markedly expand the PKD1 inhibitory chemotype inventory with eleven additional novel small molecule PKD1 inhibitors derived from our high throughput screening campaigns. The in vitro IC 50s for these eleven compounds ranged in potency from 0.4 to 6.1 μM with all of the evaluated compounds being competitive with ATP. Three of the inhibitors (CID 1893668, (1Z)-1-(3-ethyl-5-methoxy-1,3-benzothiazol-2-ylidene)propan-2-one; CID 2011756, 5-(3-chlorophenyl)-N-[4-(morpholin-4-ylmethyl)phenyl]furan-2-carboxamide; CID 5389142, (6Z)-6-[4-(3-aminopropylamino)-6-methyl-1H-pyrimidin-2-ylidene]cyclohexa-2,4-dien-1-one) inhibited phorbol ester-induced endogenous PKD1 activation in LNCaP prostate cancer cells in a concentration-dependent manner. The specificity of these compounds for PKD1 inhibitory activity was supported by kinase assay counter screens as well as by bioinformatics searches. Moreover, computational analyses of these novel cell-active PKD1 inhibitors indicated that they were structurally distinct from the previously described cell-active PKD1 inhibitors while computational docking of the new cell-active compounds in a highly conserved ATP-binding cleft suggests opportunities for structural modification. In summary, we have discovered novel PKD1 inhibitors with in vitro and cell-based inhibitory activity, thus successfully expanding the structural diversity of small molecule inhibitors available for this important pharmacological target. © 2011 Sharlow et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Sharlow, ER
Wilson, GM
Close, Ddac71@pitt.eduDAC71
Leimgruber, S
Tandon, Mmat137@pitt.eduMAT137
Reed, RB
Shun, TYtos8@pitt.eduTOS8
Wang, QJ
Wipf, Ppwipf@pitt.eduPWIPF
Lazo, JSlazo@pitt.eduLAZO
ContributionContributors NameEmailPitt UsernameORCID
Date: 5 October 2011
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 6
Number: 10
DOI or Unique Handle: 10.1371/journal.pone.0025134
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
School of Medicine > Computational and Systems Biology
School of Medicine > Pharmacology and Chemical Biology
Refereed: Yes
MeSH Headings: Adenosine Triphosphate--metabolism; Binding, Competitive; Catalytic Domain; Cell Line, Tumor; Conserved Sequence; Dose-Response Relationship, Drug; Drug Discovery--methods; Enzyme Activation--drug effects; High-Throughput Screening Assays; Humans; Models, Molecular; Molecular Sequence Data; Phorbol Esters--pharmacology; Phosphorylation--drug effects; Protein Kinase C--antagonists & inhibitors; Protein Kinase C--chemistry; Protein Kinase C--metabolism; Protein Kinase Inhibitors--chemistry; Protein Kinase Inhibitors--metabolism; Protein Kinase Inhibitors--pharmacology; Reproducibility of Results; Small Molecule Libraries--chemistry; Small Molecule Libraries--metabolism; Small Molecule Libraries--pharmacology
Other ID: NLM PMC3187749
PubMed Central ID: PMC3187749
PubMed ID: 21998636
Date Deposited: 10 Sep 2012 14:36
Last Modified: 22 Jun 2021 14:56


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