Development of a Selective, Allosteric PLD1/2 Inhibitor in a Novel Scaffold

Excerpt

A diversity-oriented synthesis approach of the neuroleptic drug halopemide, reported to be a phospholipase D2 (PLD2) inhibitor (but later shown to be a dual PLD1/2 inhibitor) afforded ML299 (CID 56593087), a potent, dual PLD1/2 selective allosteric inhibitor (cellular PLD1, IC₅₀ = 5.6 nM, cellular PLD2, IC₅₀ = 20 nM) developed within the traditionally PLD2-preferring triazasprione core. ML299 displays balanced, low nanomolar inhibition of both PLD1 and PLD2, is CNS penetrant and has improved physiochemical and dystrophia myotonica protein kinase (DMPK) properties relative to our earlier dual PLD1/2 inhibitors, making it a useful tool to probe selective PLD1 and PLD2 function in vitro and in vivo. Data here shows therapeutic relevance in virology and oncology.