Evaluating p97 inhibitor analogues for their domain selectivity and potency against the p97-p47 complex.

ABSTRACT: We previously found that p97 ATPase inhibitors 2-(2-amino-1H-benzo[d]imidazol-1-yl)-N-benzyl-8-methoxyquinazolin-4-amine (ML240) and 2-(2H-benzo[b][1,4]oxazin-4(3H)-yl)-N-benzyl-5,6,7,8-tetrahydroquinazolin-4-amine (ML241) specifically target the D2 domain of wild-type p97. In addition, one of the major p97 cofactors, p47, decreases their potencies by ∼50-fold. In contrast, N(2) ,N(4) -dibenzylquinazoline-2,4-diamine (DBeQ) targets both the D1 and D2 domains and shows only a four- to sixfold decrease in potency against the p97-p47 complex. To elucidate structure-activity relationships for the inhibitors, we screened 200 p97 inhibitor analogues for their ability to inhibit the ATPase activity of either or both of the D1 or D2 domains, as well for their effects on p47 potency. The selectivit

SUBMITTER: Fang CJ 

PROVIDER: S-EPMC4280364 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature