ML-241

Background

ML-241 is an inhibitor of valosin-containing protein (VCP, p97), which is part of an ATPase protein complex that regulates several critical cellular processes, including the proteasomal degradation of ubiquitinated proteins and autophagosome maturation. ML-241 inhibits VCP (IC₅₀ of approximately 100 nM), blocks degradation of p97-dependent proteasome substrates (IC₅₀ of approximately 3,500 nM), and impairs the endoplasmic reticulum (ER)-associated degradation pathway (1). VCP forms a hexamer with a pair of ATPase domains (D1 and D2) and an N-terminal domain that binds numerous cofactor proteins. Both ML-241 and the related inhibitor ML-240 specifically bind the D2 ATPase domain, while a second pair of inhibitors (DBeQ and NMS-873) are capable of binding and inhibiting both D1 and D2 ATPase domains (2). The p47 cofactor of VCP is shown to attenuate ML-241 inhibition of VCP by a factor of approximately 50-fold (3).