Biochem/physiol Actions

Primary TargetVCP

Reversible: yes

Cell permeable: yes

General description

A cell-permeable triazolylpyridine compound that potently inhibits VCP ATPase activity in a non-ATP-competitive manner (IC₅₀/[ATP] = 20 nM/1 mM & 30 nM/60 µM; [wt hVCP] = 10 nM) via an allosteric mechanism where the inhibitor targets the lateral tunnel formed by the D1 & D2 domains of one VCP protomer together with the D1 from the adjacent VCP molecule in the hexamer, effectively locking the protomer in a rigid conformation and thereby preventing the release of bound ADP for successful propagation of interprotomer ATP hydrolysis cycle, while being ineffective against a panel of 53 kinases or the ATPase activities of 4 other AAA (ATPase Associated with diverse/various cellular Activities) ATPases (NSF, SPATAS, VPS4B, and cdc6) and Hsp90 (by ﹤15% at 10 µM). In agreement with siRNA-mediated VCP knockdown, NMS-873 is shown to prevent VCP from extracting ubiquitinated client proteins, including cyclin E & Mcl-1, for proteasomal degradation, resulting in cellular UPR (unfold protein response) activation, autophagy induction, and eventual apoptosis in HCT-116 cultures in a dose- and time-dependent manner (0.5 to 5 µM; 8 to 72 h). Anti-cancer studies using a panel of 40 various hematological and solid tumor lines reveal wide-spread sensitivities to NMS-873-induced killings (IC₅₀ from 80 nM to 2 µM), differing in degrees than those observed with the proteasome inhibitor Bortezomib (Cat. No. Cat. No. 504314). Exhibits high clearance and low bioavailability in in vivo studies.Please note that the molecular weight for this compound is batch-specific due to variable water content.

A cell-permeable triazolylpyridine compound that potently inhibits VCP ATPase activity in a non-ATP-competitive manner (IC₅₀/[ATP] = 20 nM/1 mM & 30 nM/60 µM; [wt hVCP] = 10 nM) via an allosteric mechanism where the inhibitor targets the lateral tunnel formed by the D1 & D2 domains of one VCP protomer together with the D1 from the adjacent VCP molecule in the hexamer, effectively locking the protomer in a rigid conformation and thereby preventing the release of bound ADP for successful propagation of interprotomer ATP hydrolysis cycle, while being ineffective against a panel of 53 kinases or the ATPase activities of 4 other AAA (ATPase Associated with diverse/various cellular Activities) ATPases (NSF, SPATAS, VPS4B, and cdc6) and Hsp90 (by ﹤15% at 10 µM). In agreement with siRNA-mediated VCP knockdown, NMS-873 is shown to prevent VCP from extracting ubiquitinated client proteins, including cyclin E & Mcl-1, for proteasomal degradation, resulting in cellular UPR (unfold protein response) activation, autophagy induction, and eventual apoptosis in HCT-116 cultures in a dose- and time-dependent manner (0.5 to 5 µM; 8 to 72 h). Anti-cancer studies using a panel of 40 various hematological and solid tumor lines reveal wide-spread sensitivities to NMS-873-induced killings (IC₅₀ from 80 nM to 2 µM), differing in degrees than those observed with the proteasome inhibitor Bortezomib (Cat. No. Cat. No. 504314). Exhibits high clearance and low bioavailability in in vivo studies.

Legal Information

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

Other Notes

Magnaghi, P., et al. 2013. Nat. Chem. Biol.9, 548.Polucci, P., et al. 2013. J. Med. Chem.56, 437.

Packaging

Packaged under inert gas

10 mg in Glass bottle

Reconstitution

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.

Warning

Toxicity: Standard Handling (A)