Apoptozole - CAS 1054543-47-3
Category: Inhibitor
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Molecular Weight:
Apoptozole, also known as Apoptosis Activator VII, is an apoptosis-inducing small molecule that inhibits the ATPase activity of heat shock cognate 70 (Hsc70) and Hsp70 (Kd = 210 and 140 nM, respectively). Apoptozole dose-dependently induces apoptosis in cancer cells (IC50 = 5-7 µM).
Solid powder
4-((2-(3,5-bis(trifluoromethyl)phenyl)-4,5-bis(4-methoxyphenyl)-1H-imidazol-1-yl)methyl)benzamide; Apoptozole; Apoptosis Activator VII.
Store in a cool and dry place (or refer to the Certificate of Analysis).
Boiling Point:
703.5±70.0 °C at 760 Torr
1.33±0.1 g/cm3
Canonical SMILES:
1.Anti-leukemia activity of a Hsp70 inhibitor and its hybrid molecules.
Park SH;Kim WJ;Li H;Seo W;Park SH;Kim H;Shin SC;Zuiderweg ERP;Kim EE;Sim T;Kim NK;Shin I Sci Rep. 2017 Jun 14;7(1):3537. doi: 10.1038/s41598-017-03814-6.
In this study we examined the anti-leukemia activity of a small molecule inhibitor of Hsp70 proteins, apoptozole (Az), and hybrids in which it is linked to an inhibitor of either Hsp90 (geldanamycin) or Abl kinase (imatinib). The results of NMR studies revealed that Az associates with an ATPase domain of Hsc70 and thus blocks ATP binding to the protein. Observations made in the cell study indicated that Az treatment promotes leukemia cell death by activating caspase-dependent apoptosis without affecting the caspase-independent apoptotic pathway. Importantly, the hybrids composed of Az and geldanamycin, which have high inhibitory activities towards both Hsp70 and Hsp90, exhibit enhanced anti-leukemia activity relative to the individual inhibitors. However, the Az and imatinib hybrids have weak inhibitory activities towards Hsp70 and Abl, and display lower cytotoxicity against leukemia cells compared to those of the individual constituents. The results of a mechanistic study showed that the active hybrid molecules promote leukemia cell death through a caspase-dependent apoptotic pathway. Taken together, the findings suggest that Hsp70 inhibitors as well as their hybrids can serve as potential anti-leukemia agents.
2.A small molecule inhibitor of ATPase activity of HSP70 induces apoptosis and has antitumor activities.
Ko SK;Kim J;Na DC;Park S;Park SH;Hyun JY;Baek KH;Kim ND;Kim NK;Park YN;Song K;Shin I Chem Biol. 2015 Mar 19;22(3):391-403. doi: 10.1016/j.chembiol.2015.02.004. Epub 2015 Mar 12.
The heat shock protein HSP70 plays antiapoptotic and oncogenic roles, and thus its inhibition has been recognized as a potential avenue for anticancer therapy. Here we describe the small molecule, apoptozole (Az), which inhibits the ATPase activity of HSP70 by binding to its ATPase domain and, as a result, induces an array of apoptotic phenotypes in cancer cells. Affinity chromatography provides evidence that Az binds HSP70 but not other types of heat shock proteins including HSP40, HSP60, and HSP90. We also demonstrate that Az induces cancer cell death via caspase-dependent apoptosis by disrupting the interaction of HSP70 with APAF-1. Animal studies indicate that Az treatment retards tumor growth in a xenograft mouse model without affecting mouse viability. These studies suggest that Az will aid the development of new cancer therapies and serve as a chemical probe to gain a better understanding of the diverse functions of HSP70.
3.Probing the effect of an inhibitor of an ATPase domain of Hsc70 on clathrin-mediated endocytosis.
Cho HJ;Kim GH;Park SH;Hyun JY;Kim NK;Shin I Mol Biosyst. 2015 Oct;11(10):2763-9. doi: 10.1039/c4mb00695j.
Hsc70 is known to be involved in clathrin-mediated endocytosis (CME) by which cells take up various extracellular materials. More specifically, this protein promotes the disassembly of clathrin-coated vesicles (CCVs) by directly binding to clathrin during CME. As the ATPase activity of Hsc70 is required for its association with clathrin, we have investigated the effect of an inhibitor (apoptozole, Az) of an ATPase domain of Hsc70 on CME. The results of biochemical studies show that Az binds to Hsc70 and Hsp70 without binding to other types of heat shock proteins. Structure-activity relationship studies provide information on the structural features responsible for the inhibition of the ATPase activity of Hsc70. The results obtained from cell experiments reveal that Az disrupts the interaction of Hsc70 with clathrin in cells, thereby leading to the accumulation of transferrin in CCVs and suppression of release of free Fe(3+) from CCVs during transferrin receptor-mediated endocytosis.
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