(1R,2R)-N-([S]-1-{4-[5-broMo-2-oxo-2,3-dihydro-1H-benzo(d)iMidazol-1-yl]piperidin-1-yl}propan-2-yl)-2-phenylcyclopropanecarboxaMide

Uses

VU0359595 is an inhibitor of phospholipase D1 (PLD1) which is more than 1700 fold selective over phospholipase D2 (PLD2). This complex only binds and inhibit phospholipase D though an allosteric site, but it noes not interact with the catalytic site of phospholipase D.

Biological Activity

vu0359595 is a potent and selective inhibitor of pld1.phospholipase d (pld) isozymes mediate phospholipid hydrolysis and transphosphatidylation. until now, two mammalian isoforms of pld, pld1, and pld2, have been identified. it has been identified that pld has been implicated in a human cancer cell progression, actin cytoskeleton reorganization and cell motility [1].

in vitro

vu0359595 was an inhibitor of pld1 with an ic50 of 3.7 nm. vu0359595 showed >1,700-fold selectivity over pld2. the ic50 of was vu0359595 against pld2 was 6.4 μm [1]. preliminary evidence has demonstrated that vu0359595 showed no interaction with the catalytic site of pld, but may bind and inhibit pld through an allosteric site [1]. at 500 nm, vu0359595 significantly reduced the pld activity in astroglial cultures from wild-type mice by 58% [2]. in cells stimulated by 1% fcs, vu0359595 decreased cell proliferation in wild-type and pld2-deficient cells at a concentration of 500 nm [2]. vu0359595 (500 nm) significantly reduced cell growth in cells stimulated by either mitogen [2].

References

[1] lewis j a, scott s a, lavieri r, et al. design and synthesis of isoform-selective phospholipase d (pld) inhibitors. part i: impact of alternative halogenated privileged structures for pld1 specificity[j]. bioorganic & medicinal chemistry letters, 2009, 19(7): 1916-1920.
[2] burkhardt u, beyer s, klein j. role of phospholipases d1 and 2 in astroglial proliferation: effects of specific inhibitors and genetic deletion[j]. european journal of pharmacology, 2015, 761: 398-404.