Phospholipase D (PLD) is a enzyme responsible for hydrolyzing phosphatidylcholine into the lipid signaling molecule phosphatidic acid and choline. From a therapeutic perspective, PLD has been implicated in human cancer progression, as well as a target for neurodegenerative diseases, including Alzheimer’s. Moreover, an internal study at Biogen demonstrated that knockdown of PLD rescues the ALS phenotype in multiple Drosophila models of ALS. To further validate whether inhibiting PLD may be beneficial for the treatment of ALS, we sought to discover a brain-penetrant, small molecule inhibitor with suitable PK properties to test in an animal model. The design, discovery and optimization of chemical leads developed by a combination of ligand-based drug discovery and structure-based design will be described. A dual PLD1/PLD2 inhibitor was identified that is very potent in biochemical and cell-based assays and has suitable PK properties for in vivo studies. To capture the in vivo target engagement of PLD inhibition, a transphosphatidylation pharmacodynamic LC-MS was developed and will be described, in which the dual PLD1/PLD2 inhibitor was found to reduce PLD activity in a mouse by 15-20 fold.

Investigation of small molecule inhibitors of PLD for the treatment of ALS

2019 Fall National Meeting

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