2-(2H-benzo[b][1,4]oxazin-4(3H)-yl)-N-benzyl-5,6,7,8-tetrahydroquinazolin-4-amine

ML241 (1346528-06-0) is a potent and selective p97 AAA ATPase inhibitor, IC50=100 nM. Inhibits degradation of a p97-dependent but not p97-independent proteasome substrate in a dual-reporter cell line.1It impairs the endoplasmic reticulum-associated degradation (ERAD) pathway.1ML241 and related inhibitors (DBeQ for example) have differential responses to p97 mutants as well as the presence of cofactors suggesting the possibility of context-dependent p97 inhibitors.2,3

2-(2H-Benzo[b][1,4]oxazin-4(3H)-yl)-N-benzyl-5,6,7,8-tetrahydroquinazolin-4-amine is a p97 ATPase inhibitor.

previous study showed that both ml241 and its analog ml240 were able to inhibit p97 atpase with ic(50) values of around 100 nm. both ml241 and ml240 could inhibit degradation of a p97-dependent but not a p97-independent proteasome substrate in a dual-reporter cell line. in addition, both ml241 and ml240 could impair the endoplasmic-reticulum-associated degradation (erad) pathway. unexpectedly, ml240 could potently stimulate the accumulation of lc3-ii within minutes, inhibit cancer cell growth, and mobilize the executioner caspases 3 and 7 rapidly, whereas ml241 could not [1].

100 nm

ML-241 is an inhibitor of valosin-containing protein, 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, blocks degradation of p97-dependent proteasome substrates, and impairs the endoplasmic reticulum-associated degradation pathway. VCP forms a hexamer with a pair of ATPase domains 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 are capable of binding and inhibiting both D1 and D2 ATPase domains. The p47 cofactor of VCP is shown to attenuate ML-241 inhibition of VCP by a factor of approximately 50-fold.

[1] PROF.DR. TSUI-FEN CHOU. Structure–Activity Relationship Study Reveals ML240 and ML241 as Potent and Selective Inhibitors of p97 ATPase[J]. ChemMedChem, 2013, 8 2: 297-312. DOI:10.1002/cmdc.201200520
[2] TSUI-FEN CHOU . Specific Inhibition of p97/VCP ATPase and Kinetic Analysis Demonstrate Interaction between D1 and D2 ATPase Domains[J]. Journal of Molecular Biology, 2014, 426 15: Pages 2886-2899. DOI:10.1016/j.jmb.2014.05.022
[3] LIN GUI. Evaluating p97 inhibitor analogues for their domain‐selectivity and potency against the p97‐p47 complex[J]. FASEB Journal, 2015, 29 1. DOI:10.1096/fasebj.29.1\_supplement.721.16