Novel PLD Inhibitors


First-in-class small molecule therapeutics targeting phospholipase D (PLD) demonstrate promise as potent and selective inhibitors for viral diseases and oncology.  Vanderbilt researchers have developed small molecule selective inhibitors of phospholipase D isoforms 1 and 2, as well as molecules that inhibit both isoforms. These molecules have shown efficacy in models of influenza infection, glioblastoma, and breast cancer.  Genetic and chemical inhibition of PLD 1 and 2 exhibit negligible side effects, and these molecules have shown minimal off target toxicity and excellent DMPK profiles.


Phospholipase D is a membrane protein that catalyzes the conversion of phosphatidylcholine to phosphatidic acid, a signaling molecule that affects diverse downstream processes.  Many of these processes, including control of the cell cycle, proliferation, and intracellular trafficking, result in disease when dysfunctional.  PLD inhibitors may find utility in the following areas:

Influenza/Viral Infections: Encapsulated viruses, such as influenza, require PLD activity for:  i) entry into, ii) replication within, and iii) egress from host cells. Endocytosis and endosomal trafficking of influenza virus is an essential component of infection.  Chemical inhibition of PLD2 slows this process significantly, allowing time for a robust antiviral immune response. A549 cells treated with a PLD2 inhibitor show a significant decrease in viral titer after infection with influenza virus compared to control. Additionally, PLD1 is implicated in viral egress. Inhibition of this step in the infection process would prevent spread of the virus to uninfected cells. Tandem inhibition of both PLD isozymes may enable an effective multi-pronged approach to treating influenza infections. Whereas currently available small molecule treatments target viral proteins, PLD inhibition represents a novel approach to treatment of influenza and viral infections as it targets host factors involved in infection.

Cancer: PLD1 and 2 are involved in regulating processes essential to cancer cell survival, proliferation, and metastasis.  PLD signaling is upstream of many important oncogenes, which cannot be directly inhibited due to toxicity. The Akt pathway is one such example. Vanderbilt researchers have demonstrated that PLD2 inhibition also indirectly inhibits Akt-mediated regulation of autophagy in glioblastoma cells, leading to cell death. In contrast to direct inhibition of Akt, which results in numerous deleterious effects, inhibition through PLD is innocuous. PLD inhibitors developed at Vanderbilt show excellent CNS penetrance allowing access to the tumor. This represents a novel mode of treatment for glioblastoma multiforme, a cancer with limited treatment options and high mortality. In addition, Vanderbilt researchers have demonstrated small molecule inhibition of PLD decreases invasiveness in models of breast cancer. Ongoing research may demonstrate utility in treating other cancers.

Potential Market Size

The broad therapeutic scope of PLD inhibitors indicates a potentially significant market size. Cancer: Cancer will affect 1 in 2 men and 1 in 3 women in America. Breast cancer is the most diagnosed cancer in American women with ~230,000 new diagnoses expected in 2014 (NCI). Glioblastoma mutliforme (GBM) is a more rare cancer with ~12,000 new diagnoses each year, however, it is very difficult to treat and approximately 10% of patients will survive beyond five years after treatment.  The current drug of choice to treat GBM, Temodar, had sales of $304 million in the US in 2013. Influenza: The CDC estimates that 5-20% of the population will be infected with influenza each season resulting in approximately 200,000 hospitalizations per year. Sales for Tamiflu, the primary drug used to treat influenza infection, were $456 million in the US ($677 million worldwide) in 2013 and is predicted have stable sales for the next several years.

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

Taylor HE, Simmons GE Jr, Mathews TP, Khatua AK, Popik W, Lindsley CW, D'Aquila RT, Brown HA.  Phospholipase D1 Couples CD4+ T Cell Activation to c-Myc-Dependent Deoxyribonucleotide Pool Expansion and HIV-1 Replication.  PLoS Pathog. 2015 May 28;11(5):e1004864. doi: 10.1371/journal.ppat.1004864. eCollection 2015.

Spencer, C and Brown, HA. (2015) Biochemical characterization of a Pseudomonas aeruginosa phospholipase D. Biochemistry 54(5): 1208-1218. PMC 4337821.

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


Bruntz RC, Taylor HE, Lindsley CW, Brown HA. (2014) Phospholipase D2 mediates survival signaling through direct regulation of Akt in glioblastoma cells.  J. Biol. Chem.  289(2) : 600-616. PMC 3887188   Article Feature on the issue COVER and PAPER OF THE WEEK

Bruntz RC, Lindsley CW, Brown HA. (2014) Phospholipase D signaling pathways and phosphatidic acid as therapeutic targets in cancer.  Pharmacol. Rev.  66(4):  1033-1079. PMID 25244928

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


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

Lindsley CW and Brown HA. (2012) Phospholipase D as a therapeutic target in brain disorders.  Neuropsychopharmacology Reviews  37(1):  301-302. PMC 3238067

Licensing Contact

Karen Rufus

Tech ID: