Protein kinase D (PKD) is a novel family of the key second messenger diacylglycerol targets that can be activated by G-protein coupled receptor agonists and growth factors. The family of PKD - PKD1, 2 and 3 - plays important roles in many fundamental cellular processes. Deregulation of PKD has been implicated in multiple pathological conditions and cancer. However, the lack of a PKD-specific inhibitor has severely impeded our ability to understand PKD-specific signaling pathways and biological functions and to target it in human diseases. We have recently reported the first potent and selective small molecule inhibitor for PKD: benzoxoloazepinolone CID755673 that was identified through a high throughput screening campaign of 196,173 compounds. CID755673 is a pan-PKD inhibitor with submicromolar potencies. It was cell active and blocked the known biological actions of PKD and suppressed cancer-associated properties of proliferation, migration and invasion of prostate cancer cells. Importantly, this inhibitor was not competitive with ATP for enzyme inhibition and was highly selective for PKD when compared to at least 20 different kinases including CAMKII1, AKT, PKA and several PKC isoforms. Most critically, structural optimization of CID755673 has yielded a novel benzthiophene derivative kb-NB142-70 with low nanomolar potency and greater selectivity for PKD. We hypothesize that CID755673 can be optimized to a class of novel PKD inhibitors with unique mechanisms of action for potent and selective blockade of PKD functionality. Our long term goal is to establish a systemic approach to develop CID755673-derived probe molecules as innovative PKD inhibitors. Our proposed research strategies focus on lead optimization, mechanistic evaluation and in vivo efficacy assessment of CID755673 and its analogs.
Three specific aims are proposed, representing the first major effort towards the development of potent and selective pharmacological ablative agents for PKD:
Aim 1. Optimize CID755673 by structural modifications to access more potent and selective derivatives.
Aim 2. Determine the molecular mechanisms underlying the exquisite selectivity of CID755673 and its analogs for PKD.
Aim 3. Test the hypothesis that CID755673 and derivatives cause potent and selective blockade of PKD functionality in vivo.

Public Health Relevance

The protein kinase D family is a novel receptor of the key second messenger diacylglycerol and an emerging therapeutic target for cancer and other diseases. Further understanding the role of PKD in biological processes and targeting it in human diseases have been severely impeded by the lack of a PKD-specific inhibitor that can be readily applied to cells and in animals. We have recently discovered the first potent and selective cell-active small molecule inhibitor for PKD - CID755673. We hypothesize that CID755673 can be optimized to generate a class of novel PKD inhibitors with unique mechanisms of action for potent and selective blockade of PKD functionality. The proposed studies focus on lead optimization, mechanistic evaluation and in vivo efficacy assessment of these novel chemical entities. The successful completion of the study will lead to a novel class of PKD inhibitors that can be used as powerful tools for dissecting PKD-mediated signaling pathways and functionalities in cells and animals. It will also provide the foundation for potential future clinical development of the compounds as novel antitumor agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA142580-02
Application #
8010152
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Lees, Robert G
Project Start
2010-01-01
Project End
2014-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
2
Fiscal Year
2011
Total Cost
$294,711
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Zhang, Liyong; Zhao, Zhenlong; Xu, Shuping et al. (2017) Androgen suppresses protein kinase D1 expression through fibroblast growth factor receptor substrate 2 in prostate cancer cells. Oncotarget 8:12800-12811
Roy, Adhiraj; Ye, Jing; Deng, Fan et al. (2017) Protein kinase D signaling in cancer: A friend or foe? Biochim Biophys Acta 1868:283-294
Xu, Xuehua; Yun, Michelle; Wen, Xi et al. (2016) Quantitative Monitoring Spatiotemporal Activation of Ras and PKD1 Using Confocal Fluorescent Microscopy. Methods Mol Biol 1407:307-23
Xu, Q; Deng, F; Xing, Z et al. (2016) Long non-coding RNA C2dat1 regulates CaMKII? expression to promote neuronal survival through the NF-?B signaling pathway following cerebral ischemia. Cell Death Dis 7:e2173
Xu, Q; Deng, F; Qin, Y et al. (2016) Long non-coding RNA regulation of epithelial-mesenchymal transition in cancer metastasis. Cell Death Dis 7:e2254
Qu, Q; Zeng, F; Liu, X et al. (2016) Fatty acid oxidation and carnitine palmitoyltransferase I: emerging therapeutic targets in cancer. Cell Death Dis 7:e2226
Liou, Geou-Yarh; Döppler, Heike; Braun, Ursula B et al. (2015) Protein kinase D1 drives pancreatic acinar cell reprogramming and progression to intraepithelial neoplasia. Nat Commun 6:6200
Tandon, Manuj; Salamoun, Joseph M; Carder, Evan J et al. (2015) SD-208, a novel protein kinase D inhibitor, blocks prostate cancer cell proliferation and tumor growth in vivo by inducing G2/M cell cycle arrest. PLoS One 10:e0119346
Xu, Xuehua; Gera, Nidhi; Li, Hongyan et al. (2015) GPCR-mediated PLC??/PKC?/PKD signaling pathway regulates the cofilin phosphatase slingshot 2 in neutrophil chemotaxis. Mol Biol Cell 26:874-86
Wang, Pan; Han, Limin; Shen, Hong et al. (2014) Protein kinase D1 is essential for Ras-induced senescence and tumor suppression by regulating senescence-associated inflammation. Proc Natl Acad Sci U S A 111:7683-8

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