DBeQ

DBeQ（CAS号177355-84-9）是p97 ATP酶的选择性和可逆抑制剂(IC50 = 1.5 μM),能够迅速诱导caspase-3和caspase-9.

p97,亦称VCP(酵母中称Cdc48),是AAA家族的六聚体ATP酶,在膜融合后能使SNARE蛋白去组装[1].其参与同型膜融合\蛋白降解和膜结合转录因子的活化[2].p97是真核生物胞质中最丰富的蛋白之一,其隔离酶(segregase)功能与许多生物学过程相关,如内质网相关的降解(ERAD)\线粒体相关的降解\泛素融合降解\同型膜融合\细胞周期调控\自噬和转录因子调节[3].

DBeQ能阻断内质网相关降解(ERAD)受体的降解,也能阻断自噬体成熟,二者在癌症治疗中非常重要[4, 5].DBeQ 是ATP敏感性的,选择性靶向D1和D2结构域,ODD-Luc IC50 56 μM\Luc-ODC IC50 45 μM\UbG76VGFP IC50 2.3 μM,相比于其它噻唑啉类受p47的影响较小[6, 7].

参考文献：
1.  Zhang, X. et al. "Structure of the AAA ATPase p97". Molecular cell 2000, 6 (6): 1473–84.
2.  Madsen, L. et al. "New ATPase regulators--p97 goes to the PUB.". Int J Biochem Cell Biol 2009, 41 (12): 2380–8.
3.  Eli Chapman. et al. “Inhibitors of the AAA+ Chaperone p97”. Molecules 2015, 20(2), 3027-3049.
4.  Liu, Y. Et al. “VCP/p97,down-regulated by microRNA-129-5p, could regulate the progression of hepatocellular carcinoma”. PLoS One 2012, 7, e35800.
5.  Lagu, M.N. et al. “Proteomic profiling of a mouse model for ovarian granulosa cell tumor identifies VCP as a highly sensitive serum tumor marker in several human cancers.” PLoS One 2012, 7, e42470.
6.  Fang, C.J. et al. “Evaluating p97 inhibitor analogues for their domain selectivity and potency against the p97–p47 complex.” Chem. Med. Chem. 2014.
7.  Chou, T.F. et al. “Specific inhibition of p97/VCP ATPase and kinetic analysis demonstrated interaction between D1 and D2 ATPase domains.” J. Mol. Biol. 2014, 426, 2886–2899.