Development of small molecule inhibitors of protein kinase D

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DESCRIPTION (provided by applicant): 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.