2. Academic Validation
  3. A small molecule inhibitor of ATPase activity of HSP70 induces apoptosis and has antitumor activities

A small molecule inhibitor of ATPase activity of HSP70 induces apoptosis and has antitumor activities

  • Chem Biol. 2015 Mar 19;22(3):391-403. doi: 10.1016/j.chembiol.2015.02.004.
Sung-Kyun Ko 1,  Jiyeon Kim 2,  Deuk Chae Na 3,  Sookil Park 1,  Seong-Hyun Park 1,  Ji Young Hyun 1,  Kyung-Hwa Baek 1,  Nam Doo Kim 4,  Nak-Kyoon Kim 5,  Young Nyun Park 3,  Kiwon Song 2,  Injae Shin 6
Affiliations

Affiliations

  • 1 Center for Biofunctional Molecules, Department of Chemistry, Yonsei University, Seoul 120-749, Korea.
  • 2 Department of Biochemistry, Yonsei University, Seoul 120-749, Korea.
  • 3 Department of Pathology, Yonsei University College of Medicine, Seoul 120-752, Korea.
  • 4 New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 706-010, Korea.
  • 5 Advanced Analysis Center, Korea Institute of Science and Technology, Seoul 136-791, Korea.
  • 6 Center for Biofunctional Molecules, Department of Chemistry, Yonsei University, Seoul 120-749, Korea. Electronic address: [email protected].
PMID: 25772468 DOI: 10.1016/j.chembiol.2015.02.004
Abstract

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.

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