ML241 - CAS 1346528-06-0
Catalog number: B0084-475332
Category: Inhibitor
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ML241 is a selective p97 ATPase inhibitor and IC50 value is 100 nM. It can inhibit degradation of a p97-dependent but not a p97-independent proteasome substrate in a dual-reporter cell line. ML241 may be a novel agent for the treatment of cancer.
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Catalog Number Size Price Stock Quantity
B0084-475332 100 mg $348 In stock
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Related CAS:
2070015-13-1 (HCl)
Solid powder
2-(2H-benzo[b][1,4]oxazin-4(3H)-yl)-N-benzyl-5,6,7,8-tetrahydroquinazolin-4-amine; ML241; ML-241; ML 241
Soluble in DMSO
-20°C Freezer
Quality Standard:
In-house standard
Shelf Life:
2 month in rt, long time
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1.Structure-activity relationship study reveals ML240 and ML241 as potent and selective inhibitors of p97 ATPase.
Chou TF;Li K;Frankowski KJ;Schoenen FJ;Deshaies RJ ChemMedChem. 2013 Feb;8(2):297-312. doi: 10.1002/cmdc.201200520. Epub 2013 Jan 11.
To discover more potent p97 inhibitors, we carried out a structure-activity relationship study of the quinazoline scaffold previously identified from our HTS campaigns. Two improved inhibitors, ML240 and ML241, inhibit p97 ATPase with IC(50) values of 100 nM. Both compounds inhibited degradation of a p97-dependent but not a p97-independent proteasome substrate in a dual-reporter cell line. They also impaired the endoplasmic-reticulum-associated degradation (ERAD) pathway. Unexpectedly, ML240 potently stimulated accumulation of LC3-II within minutes, inhibited cancer cell growth, and rapidly mobilized the executioner caspases 3 and 7, whereas ML241 did not. The behavior of ML240 suggests that disruption of the protein homeostasis function of p97 leads to more rapid activation of apoptosis than is observed with a proteasome inhibitor. Further characterization revealed that ML240 has broad antiproliferative activity toward the NCI-60 panel of cancer cell lines, but slightly lower activity toward normal cells. ML240 also synergizes with the proteasome inhibitor MG132 to kill multiple colon cancer cell lines. Meanwhile, both probes have low off-target activity toward a panel of protein kinases and central nervous system targets.
2.Specific inhibition of p97/VCP ATPase and kinetic analysis demonstrate interaction between D1 and D2 ATPase domains.
Chou TF;Bulfer SL;Weihl CC;Li K;Lis LG;Walters MA;Schoenen FJ;Lin HJ;Deshaies RJ;Arkin MR J Mol Biol. 2014 Jul 29;426(15):2886-99. doi: 10.1016/j.jmb.2014.05.022. Epub 2014 May 27.
The p97 AAA (ATPase associated with diverse cellular activities), also called VCP (valosin-containing protein), is an important therapeutic target for cancer and neurodegenerative diseases. p97 forms a hexamer composed of two AAA domains (D1 and D2) that form two stacked rings and an N-terminal domain that binds numerous cofactor proteins. The interplay between the three domains in p97 is complex, and a deeper biochemical understanding is needed in order to design selective p97 inhibitors as therapeutic agents. It is clear that the D2 ATPase domain hydrolyzes ATP in vitro, but whether D1 contributes to ATPase activity is controversial. Here, we use Walker A and B mutants to demonstrate that D1 is capable of hydrolyzing ATP and show for the first time that nucleotide binding in the D2 domain increases the catalytic efficiency (kcat/Km) of D1 ATP hydrolysis 280-fold, by increasing kcat 7-fold and decreasing Km about 40-fold. We further show that an ND1 construct lacking D2 but including the linker between D1 and D2 is catalytically active, resolving a conflict in the literature. Applying enzymatic observations to small-molecule inhibitors, we show that four p97 inhibitors (DBeQ, ML240, ML241, and NMS-873) have differential responses to Walker A and B mutations, to disease-causing IBMPFD mutations, and to the presence of the N domain binding cofactor protein p47.
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