Discovery of Phospholipase D Inhibitors with Improved Drug-like Properties and Central Nervous System Penetrance

Abstract

Phospholipase D (PLD) is a phospholipase 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, knockdown of PLD rescues the ALS phenotype in multiple Drosophila models of ALS (amyotrophic lateral sclerosis) and displays modest motor benefits in an SOD1 ALS mouse model. To further validate whether inhibiting PLD is beneficial for the treatment of ALS, a brain penetrant small molecule inhibitor with suitable PK properties to test in an ALS animal model is needed. Using a combination of ligand-based drug discovery and structure-based design, a dual PLD1/PLD2 inhibitor was discovered that is single digit nanomolar in the Calu-1 cell assay and has suitable PK properties for in vivo studies. To capture the in vivo measurement of PLD inhibition, a transphosphatidylation pharmacodynamic LC-MS assay was developed, in which a dual PLD1/PLD2 inhibitor was found to reduce PLD activity by 15−20-fold.

Transcriptome-wide N6-methyladenosine modification profiling of long non-coding RNAs in patients with recurrent implantation failure

“…Choline metabolism is related to Phospholipase D signaling pathway. Phospholipase D (PLD) is a phospholipase enzyme responsible for hydrolyzing phosphatidylcholine into the lipid signaling molecule, phosphatidic acid and choline (42). Choline is a micronutrient and a methyl donor (43).…”

Carrier-Mediated Delivery of Low-Molecular-Weight N-Containing Drugs across the Blood–Brain Barrier or the Blood–Retinal Barrier Using the Proton-Coupled Organic Cation Antiporter

“…Most CNS drugs have structurally incorporated N-containing groups in their molecules. Brain-penetrating compounds (1-10) recently reported in the last year or two also possess N-containing groups [Figure 3] [ [21][22][23][24][25][26][27][28][29][30]. This fact suggests that N-containing groups act as the transporter recognition unit for a specific type of cation transporter at the BBB.…”

Phospholipase D, a Novel Therapeutic Target Contributes to the Pathogenesis of Neurodegenerative and Neuroimmune Diseases

“…In the mouse model of ALS, there is a corresponding increase in PLD1 levels, which correlates with early-onset ALS in postmortem human tissues [ 72 ]. In the drosophila model of ALS, the downregulation of PLD improves degenerative characteristics [ 73 ]. Lacoangeli et al [ 74 ] conducted a meta-analysis using a published study of postmortem gene expression in motor neurons from ALS patients, suggesting that the PLD1 pathway may play a role in regulating the ALS phenotype.…”