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

Chemistry & Biology
Sung-Kyun KoInjae Shin

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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Citations

Jan 16, 2016·Journal of the American Chemical Society·Jaeyoung PaiInjae Shin
Mar 5, 2016·Cell Chemical Biology·Liza ShresthaGabriela Chiosis
May 12, 2016·Heart Failure Reviews·George H KunkelSuresh C Tyagi
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Sep 24, 2016·Molecular Neurobiology·Sara D ReisJorge M A Oliveira
Apr 20, 2017·Chembiochem : a European Journal of Chemical Biology·Ji Young HyunInjae Shin
Dec 1, 2015·Chemical Science·Seong-Hyun ParkInjae Shin
Sep 22, 2017·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Junji MiyakoshiShuichi Kawai
Sep 15, 2018·The Journal of Biological Chemistry·Jason E Gestwicki, Hao Shao
Jun 30, 2019·Chemistry, an Asian Journal·Seong-Hyun ParkInjae Shin
Aug 14, 2019·PloS One·Patrick Kim ChiawJason C Young
Jan 2, 2016·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Elizabeth RoundhillSusan Burchill
Jun 21, 2019·CNS Neuroscience & Therapeutics·Long-Long LuoYong-Ting Wang
Oct 11, 2019·Proceedings of the National Academy of Sciences of the United States of America·Akhouri Kishore RaghawanGhanshyam Swarup
Aug 24, 2019·IUBMB Life·Reyhaneh Moradi-MarjanehMahdi Moradi Marjaneh
Jan 21, 2020·Chemical Society Reviews·Sangshan PengJonathan L Sessler
Mar 4, 2020·Cells·Zarema AlbakovaAlexander M Sapozhnikov
Jun 16, 2017·Scientific Reports·Seong-Hyun ParkInjae Shin
Feb 13, 2019·Chemical Science·Sang-Hyun ParkInjae Shin
Oct 2, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Xiaoying HeJunying Miao
Feb 23, 2021·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Yiming ZhangYuhua Song
Aug 31, 2020·International Journal of Biological Macromolecules·Masoud PiraliHossein Ghafouri
Sep 28, 2018·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Dhaval SanchalaYogesh A Kulkarni
Apr 6, 2021·Frontiers in Immunology·Zarema AlbakovaAlexander Sapozhnikov
Apr 28, 2021·European Journal of Medicinal Chemistry·Ziqian WangZhichao Zhang
Jul 9, 2021·Organic & Biomolecular Chemistry·Hui LiInjae Shin
Jul 16, 2021·Chembiochem : a European Journal of Chemical Biology·Sang-Hyun ParkInjae Shin
Aug 25, 2020·Analytical Chemistry·Sang-Hyun ParkInjae Shin
Aug 25, 2021·International Journal of Biological Macromolecules·Vaha Akbary MoghaddamAsadollah Mohammadi

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