3-[[2-メチル-4′-(メチルスルホニル)-4-ビフェニリルオキシ]メチル]-4-(3-ピリジル)-5-(シクロペンチルチオ)-4H-1,2,4-トリアゾール

説明

The p97 AAA (ATPase associated with diverse cellular activities) is a ubiquitin-selective chaperone known to play a critical role in the degradation of misfolded membrane and secretory proteins and has been linked to various cellular processes that require unfolding and disassembly of protein complexes. Valosin-containing protein (VCP), also known as VCP/p97, is an AAA ATPase family member that serves as an integral component of the ubiquitin fusion degradation pathway and is overexpressed in many tumor types. NMS-873 is a VCP inhibitor (IC₅₀ = 24 nM) that demonstrates potent selectivity for VCP/p97 compared to a panel of other AAA ATPases, Hsp90, and 53 additional analyzed kinases (IC₅₀s >10 μM). It has been shown to inhibit the proliferation of HCT116 cancer cells with an IC₅₀ value of 380 nM.

使用

NMS-873 is a potent and specific VCP inhibitor, which has shown to activate the unfolded protein response, interfere with autophagy and induce cancer cell death.

Biochem/physiol Actions

NMS-873 is a selective allosteric non–ATP-competitive inhibitor of the AAA ATPase family member valosine containing protein (VCP), also known as p97 (VCP/p97), an integral component of the ubiquitin fusion degradation (UFD) pathway. VCP/p97 plays a role in degradation of misfolded proteins, Golgi membrane reassembly, membrane transport, myofibril assembly, autophagosome maturation, and cell division, and is overexpressed in many tumor types. NMS-873 is the most potent and specific VCP inhibitor described to date. NMS-873 has an IC50 of 30 nM for VCP/p97 compared to IC50 >10 μM against all of the AAA ATPases, HSP90 or the 53 kinases analyzed. NMS-873 inhibited proliferation of HCT116 cancer cell line cells with an IC50 value of 400 nM.