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1.  Inducible silencing of protein kinase D3 inhibits secretion of tumor-promoting factors in prostate cancer 
Molecular Cancer Therapeutics  2012;11(7):1389-1399.
Protein kinase D acts as a major mediator of several signaling pathways related to cancer development. Aberrant PKD expression and activity have been demonstrated in multiple cancers, and novel PKD inhibitors show promising anti-cancer activities. Despite these advances, the mechanisms through which PKD contributes to the pathogenesis of cancer remain unknown. Here, we establish a novel role for PKD3, the least studied member of the PKD family, in the regulation of prostate cancer cell growth and motility through modulation of secreted tumor-promoting factors. Using both a stable inducible knockdown cell model and a transient knockdown system employing multiple siRNAs, we demonstrate that silencing of endogenous PKD3 significantly reduces prostate cancer cell proliferation, migration, and invasion. Additionally, conditioned medium from PKD3 knockdown cells exhibits less migratory potential compared to that from control cells. Further analysis indicated that depletion of PKD3 blocks secretion of multiple key tumor-promoting factors including MMP-9, IL-6, IL-8, and GROα, but does not alter mRNA transcript levels for these factors, implying impairment of the secretory pathway. More significantly, inducible depletion of PKD3 in a subcutaneous xenograft model suppresses tumor growth and decreases levels of intratumoral GROα in mice. These data validate PKD3 as a promising therapeutic target in prostate cancer and shed light on the role of secreted tumor-promoting factors in prostate cancer progression.
doi:10.1158/1535-7163.MCT-11-0887
PMCID: PMC3392457  PMID: 22532599
Protein kinase D; prostate cancer; cytokines; secretion; inducible knockdown
2.  Protein kinase D as a potential new target for cancer therapy 
Biochimica et biophysica acta  2010;1806(2):183-192.
Protein kinase D is a novel family of serine/threonine kinases and diacylglycerol receptors that belongs to the calcium/calmodulin-dependent kinase superfamily. Evidence has established that specific PKD isoforms are dysregulated in several cancer types, and PKD involvement has been documented in a variety of cellular processes important to cancer development, including cell growth, apoptosis, motility, and angiogenesis. In light of this, there has been a recent surge in the development of novel chemical inhibitors of PKD. This review focuses on the potential of PKD as a chemotherapeutic target in cancer treatment and highlights important recent advances in the development of PKD inhibitors.
doi:10.1016/j.bbcan.2010.05.003
PMCID: PMC2947595  PMID: 20580776
Protein kinase D; cancer; small molecule inhibitors
3.  Friction Anisotropy with Respect to Topographic Orientation 
Scientific Reports  2012;2:988.
Friction characteristics with respect to surface topographic orientation were investigated using surfaces of different materials and fabricated with grooves of different scales. Scratching friction tests were conducted using a nano-indentation-scratching system with the tip motion parallel or perpendicular to the groove orientation. Similar friction anisotropy trends were observed for all the surfaces studied, which are (1) under a light load and for surfaces with narrow grooves, the tip motion parallel to the grooves offers higher friction coefficients than does that perpendicular to them, (2) otherwise, equal or lower friction coefficients are found under this motion. The influences of groove size relative to the diameter of the mating tip (as a representative asperity), surface contact stiffness, contact area, and the characteristic stiction length are discussed. The appearance of this friction anisotropy is independent of material; however, the boundary and the point of trend transition depend on material properties.
doi:10.1038/srep00988
PMCID: PMC3523288  PMID: 23248751
4.  A protein kinase C/protein kinase D pathway protects LNCaP prostate cancer cells from phorbol ester-induced apoptosis by promoting ERK1/2 and NF-κB activities 
Carcinogenesis  2011;32(8):1198-1206.
Phorbol esters such as phorbol 12-myristate 13-acetate (PMA) induce apoptosis in many tumor cells including the androgen-sensitive LNCaP prostate cancer cells. Although phorbol ester-induced apoptotic pathways have been well characterized, little is known of the pro-survival pathways modulated by these agents. We now provide experimental evidence to indicate that protein kinase D (PKD) promotes survival signals in LNCaP cells in response to PMA treatment. Knockdown of endogenous PKD1 or PKD2 decreased extracellular signal-regulated kinase (ERK) 1/2 and nuclear factor-kappaB (NF-κB)-dependent transcriptional activities and potentiated PMA-induced apoptosis, whereas overexpression of wild-type PKD1 enhanced ERK1/2 activity and suppressed PMA-induced apoptosis. PMA caused rapid activation, followed by progressive downregulation of endogenous PKD1 in a time- and concentration-dependent manner. The downregulation of PKD1 was dependent on the activity of protein kinase C (PKC), but not that of PKD. Selective depletion of endogenous PKC isoforms revealed that both PKCδ and PKCϵ were required for PKD1 activation and subsequent downregulation. Further analysis showed that the downregulation of PKD1 was mediated by a ubiquitin–proteasome degradation pathway, inhibition of which correlated to increased cell survival. In summary, our data indicate that PKD1 is activated and downregulated by PMA through a PKC-dependent ubiquitin–proteasome degradation pathway, and the activation of PKD1 or PKD2 counteracts PMA-induced apoptosis by promoting downstream ERK1/2 and NF-κB activities in LNCaP prostate cancer cells.
doi:10.1093/carcin/bgr113
PMCID: PMC3149210  PMID: 21665893
5.  Synthesis and Structure-Activity Relationships of Benzothienothiazepinone Inhibitors of Protein Kinase D 
ACS medicinal chemistry letters  2011;2(2):154-159.
Protein kinase D (PKD) is a member of a novel family of serine/threonine kinases that regulate fundamental cellular processes. PKD is implicated in the pathogenesis of several diseases, including cancer. Progress in understanding the biological functions and therapeutic potential of PKD has been hampered by the lack of specific inhibitors. The benzoxoloazepinolone CID755673 was recently identified as the first potent and selective PKD inhibitor. The study of structure-activity relationships (SAR) of this lead structure led to further improvements in PKD1 potency. We describe herein the synthesis and biological evaluation of novel benzothienothiazepinone analogs. We achieved a ten-fold increase in the in vitro PKD1 inhibitory potency for the second generation lead kb-NB142-70 and accomplished a transition to an almost equally potent novel pyrimidine scaffold, while maintaining excellent target selectivity. These promising results will guide the design of pharmacological tools to dissect PKD function and pave the way for the development of potential anti-cancer agents.
doi:10.1021/ml100230n
PMCID: PMC3100199  PMID: 21617763
Protein kinase D; small molecule inhibitor; benzothienothiazepinone; pyrimidines; CID755673
6.  Design, Synthesis, and Biological Evaluation of PKD Inhibitors 
Pharmaceutics  2011;3(2):186-228.
Protein kinase D (PKD) belongs to a family of serine/threonine kinases that play an important role in basic cellular processes and are implicated in the pathogenesis of several diseases. Progress in our understanding of the biological functions of PKD has been limited due to the lack of a PKD-specific inhibitor. The benzoxoloazepinolone CID755673 was recently reported as the first potent and kinase-selective inhibitor for this enzyme. For structure-activity analysis purposes, a series of analogs was prepared and their in vitro inhibitory potency evaluated.
doi:10.3390/pharmaceutics3020186
PMCID: PMC3261798  PMID: 22267986
protein kinase D; small molecule inhibitor; benzothienothiazepinone; pyrimidines; CID755673; thiazepinothiophenopyrimidinone
7.  Design, Synthesis, and Biological Evaluation of PKD Inhibitors 
Pharmaceutics  2011;3(2):186-228.
Protein kinase D (PKD) belongs to a family of serine/threonine kinases that play an important role in basic cellular processes and are implicated in the pathogenesis of several diseases. Progress in our understanding of the biological functions of PKD has been limited due to the lack of a PKD-specific inhibitor. The benzoxoloazepinolone CID755673 was recently reported as the first potent and kinase-selective inhibitor for this enzyme. For structure-activity analysis purposes, a series of analogs was prepared and their in vitro inhibitory potency evaluated.
doi:10.3390/pharmaceutics3020186
PMCID: PMC3261798  PMID: 22267986
protein kinase D; small molecule inhibitor; benzothienothiazepinone; pyrimidines; CID755673; thiazepinothiophenopyrimidinone
8.  Discovery of Diverse Small Molecule Chemotypes with Cell-Based PKD1 Inhibitory Activity 
PLoS ONE  2011;6(10):e25134.
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 IC50s 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.
doi:10.1371/journal.pone.0025134
PMCID: PMC3187749  PMID: 21998636
9.  Novel protein kinase D inhibitors cause potent arrest in prostate cancer cell growth and motility 
BMC Chemical Biology  2010;10:5.
Background
Protein kinase D (PKD) has been implicated in a wide range of cellular processes and pathological conditions including cancer. However, targeting PKD therapeutically and dissecting PKD-mediated cellular responses remains difficult due to lack of a potent and selective inhibitor. Previously, we identified a novel pan-PKD inhibitor, CID755673, with potency in the upper nanomolar range and high selectivity for PKD. In an effort to further enhance its selectivity and potency for potential in vivo application, small molecule analogs of CID755673 were generated by modifying both the core structure and side-chains.
Results
After initial activity screening, five analogs with equal or greater potencies as CID755673 were chosen for further analysis: kb-NB142-70, kb-NB165-09, kb-NB165-31, kb-NB165-92, and kb-NB184-02. Our data showed that modifications to the aromatic core structure in particular significantly increased potency while retaining high specificity for PKD. When tested in prostate cancer cells, all compounds inhibited PMA-induced autophosphorylation of PKD1, with kb-NB142-70 being most active. Importantly, these analogs caused a dramatic arrest in cell proliferation accompanying elevated cytotoxicity when applied to prostate cancer cells. Cell migration and invasion were also inhibited by these analogs with varying potencies that correlated to their cellular activity.
Conclusions
Throughout the battery of experiments, the compounds kb-NB142-70 and kb-NB165-09 emerged as the most potent and specific analogs in vitro and in cells. These compounds are undergoing further testing for their effectiveness as pharmacological tools for dissecting PKD function and as potential anti-cancer agents in the treatment of prostate cancer.
doi:10.1186/1472-6769-10-5
PMCID: PMC2873968  PMID: 20444281

Results 1-9 (9)