Delving into the Latest Updates on CAY-10593 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

PLD1

Mechanism

PLD1 inhibitors(phospholipase D1 inhibitors)

Therapeutic Areas

Neoplasms

Active Indication

Neoplasms

Inactive Indication-

Originator Organization

Vanderbilt University School of Medicine

Active Organization

Vanderbilt University School of Medicine

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC26H27ClN4O2

InChIKeyDRIMIUYGTDAQOX-KRWDZBQOSA-N

CAS Registry1130067-06-9

We previously reported that the thiol proteinase inhibitor, E-64-d, ameliorated amyloid β (Aβ)-induced reduction of soluble amyloid precursor protein α (sAPPα) secretion by reversing ceramide-induced protein kinase C down-regulation in SH-SY5Y neuroblastoma cells. In the present study, we showed that Aβ (1-42) peptide enhanced diacylglycerol (DAG) production by phospholipase D (PLD) activation in these cells. We subsequently examined whether PLD was involved in Aβ-induced reduction of sAPPα secretion and showed that 2 μM CAY10593, which selectively inhibits PLD2, ameliorated reduction of sAPPα secretion, whereas 50 nM CAY10593, which selectively inhibits PLD1, did not. Moreover, 50 µM propranolol, a phosphatidic acid phosphohydrolase inhibitor, also ameliorated Aβ-induced reduction of sAPPα secretion, suggesting that DAG may be responsible for Aβ-induced reduction of sAPPα. We subsequently examined whether DAG affects sAPPα secretion and showed that a DAG analog reduced sAPPα secretion in SH-SY5Y cells. In addition, DAG enhanced ceramide production by stimulating neutral sphingomyelinase (N-SMase) activity. We previously demonstrated that Aβ stimulates N-SMase activity in SH-SY5Y cells. Here, we showed that inhibition of PLD2 by 2 μM CAY10593 suppressed Aβ-induced N-SMase activation. Taken together, the results suggest that DAG produced through the PLD pathway is involved in Aβ-induced reduction of sAPPα secretion in SH-SY5Y cells.

100 Deals associated with CAY-10593

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