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Novel PLD Inhibitors
Vanderbilt researchers have created the first isoform-selective phospholipase D (PLD) inhibitors. These highly potent inhibitors can significantly reduce PLD activity, creating a new class of anti-metastatic agents.
Phospholipase D (PLD) is an enzyme located in the plasma membrane. PLD and the messenger it generates, phosphatidic acid (PA), have been implicated in many cell biological processes, which ultimately link PLD to a number of human diseases including cancer, diabetes, myocardial disease, neurodegenerative disorders, and infectious diseases. PLD activity has been shown to be up-regulated in several cancers, and over-expression of PLD has been shown to lead to neoplastic transformation, conversion of normal tissue into a malignant tumor, as well as tumor migration. Interestingly, different cancers have differential isoform-selective PLD involvement such that even within different breast cancers, PLD1 and PLD2 may be playing different roles.
Vanderbilt researchers have designed and synthesized the first isoenzyme-selective small molecule PLD inhibitors. This group has created three classes of selective PLD inhibitors including dual PLD inhibitors, an isoform-selective PLD1 inhibitor and an isoform-selective PLD2 inhibitor. These first in class inhibitors significantly decreased the ability of three invasive cell lines to migrate in trans-well invasion assays. Isoform-selective PLD1 inhibitors were also able to significantly block cell migration in 4T1 cells, even at low concentrations, whereas isoform selective PLD2 inhibitors did not have this affect in 4T1 cells, highlighting the fact that PLD isoforms may have different roles depending on the particular cancer mutation. Vanderbilt researchers have confirmed and published this finding using siRNA knockdowns (Nature Chem. Bio. 2009, Scott et al.). These results suggest PLD1 may have a specific role in cell migration in 4T1 cells and may be a novel target for cancer therapy. Moreover, these results suggest that PLD inhibitors could be specifically selected to target and personalize cancer therapy. This would allow the physician to specifically target therapy for the specific cancers and even specific cancer mutations.
Vanderbilt researchers are currently performing DMPK studies, but preliminary results suggest that PLD inhibitors are nontoxic in whole animals. Taken together, these results suggest that PLD isoform-selective inhibitors may be a great potential therapy for cancer such that treatment can be specifically targeted for the specific cancer and even the specific mutation within that cancer.
Potential Market Size
Cancer is the second leading cause of death in the United States, accounting for 23.1 % of all deaths in 2006. It is estimated that about 1.5 million new cases of cancer will be diagnosed in 2009. Cancers of the prostate and breast will be the most frequently diagnosed cancers in men and women, respectively, followed by lung and colorectal cancers. Cancers of the brain/other nervous system are the second leading cause of cancer death in children 0-14. These statistics are from the US Mortality Data 2006, National Center for Health Statistics, Centers for Disease Control and Prevention, 2009.
Current Competitive Products
Currently there are no therapies targeted at PLD, and thus these compounds would be a first in class. Patients are currently treated with various types of chemotherapies and combinations of therapies including Alkylating agents, which act by directly damaging DNA, Antimetabolites, which interfere with DNA and RNA growth, Anthracyclines, which interfere with enzymes involved in DNA replication, and topoisomerases, which inhibit the strands of DNA from separating during replication. Most of these therapies are general and affect all cells, thus making side effects common and often life altering. There is a real need for new classes of therapies that are selective and effective such that cancer can be targeted and treated without many of the adverse side effects.
Vanderbilt is looking to partner with industry to continue studies and explore the role of isoform-selective PLD inhibitors as potential cancer therapies. Specifically Vanderbilt researchers are evaluating the effects of these compounds on panels of various human cancer cell lines. Additionally, Vanderbilt researchers would also like to validate these compounds in xenograph human glioblastoma mouse models.
Intellectual Property Status
Vanderbilt holds patent applications for composition of novel chemical series for PLD1-selective, PLD2-selective and dual PLD inhibitors, as well as method of use for these inhibitors.
Infectious Disease (influenza)
Oguin TH, Sharma S, Stuart AD, Duan S, Scott S, Jones CK, Daniels JS, Lindsley CW, Thomas PG, Brown HA. (2014) Phospholipase D facilitates efficient entry of influenza virus allowing escape from innate immune inhibition. J. Biol. Chem. 289(37): 25405-25417. PMC 4162146
O'Reilly MC, Oguin TH,3rd, Scott SA, Thomas PG, Locuson CW, Morrison RD, Daniels JS, Brown HA, Lindsley CW. (2014) Discovery of a highly selective PLD2 inhibitor (ML395): a new probe with improved physiochemical properties and broad spectrum antiviral activity against influenza strains. Chem. Med. Chem. Sep 10. [Epub ahead of print]. PMID 25210004
Scott SA, Spencer CT, O'Reilly MC, Brown KA, Lavieri RL, Cho C-H, Jung D-I, Larock RC, Brown HA, Lindsley CW. (2014) Discovery of desketoraloxifene analogs as inhibitors of mammalian, Pseudomonas aeruginosa and NAPE phospholipase D enzymes. ACS Chem. Biol. [Epub ahead of print] Nov.10, 2014. doi:10.1021/cb500828m
Article Feature on the issue COVER and PAPER OF THE WEEK. See first-author profile at http://www.jbc.org/content/289/2/600/suppl/DCAuthor profile
Scott SA, Mathews TP, Ivanova PT, Lindsley CW, Brown HA. (2014) Chemical modulation of glycerolipid signaling and metabolic pathways. Biochim. Biophys. Acta - Molec. Cell Biol. Lipids 1841: 1060-1084. PMC 4069240
>Scott SA, Selvy PE, Buck JR, Cho HP, Criswell TL, Thomas AL, Armstrong MD, Arteaga CL, Lindsley CW, and Brown HA. (2009) Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness. Nature Chem. Biol. 5(2): 108-117. PMID19136975
Inventors:H. Alex Brown