%0 Journal Article
%A Bhatia, Sanil
%A Diedrich, Daniela
%A Frieg, Benedikt
%A Ahlert, Heinz
%A Stein, Stefan
%A Bopp, Bertan
%A Lang, Franziska
%A Zang, Tao
%A Kröger, Tobias
%A Ernst, Thomas
%A Kögler, Gesine
%A Krieg, Andreas
%A Lüdeke, Steffen
%A Kunkel, Hana
%A Rodrigues Moita, Ana J.
%A Kassack, Matthias U.
%A Marquardt, Viktoria
%A Opitz, Friederike V.
%A Oldenburg, Marina
%A Remke, Marc
%A Babor, Florian
%A Grez, Manuel
%A Hochhaus, Andreas
%A Borkhardt, Arndt
%A Groth, Georg
%A Nagel-Steger, Luitgard
%A Jose, Joachim
%A Kurz, Thomas
%A Gohlke, Holger
%A Hansen, Finn K.
%A Hauer, Julia
%T Targeting HSP90 dimerization via the C-terminus is effective in imatinib resistant CML and lacks heat shock response
%J Blood
%V 132
%N 3
%@ 1528-0020
%C Stanford, Calif.
%I HighWire Press
%M FZJ-2018-02988
%P 307-320
%D 2018
%X Heat shock protein 90 (HSP90) stabilizes many client proteins including BCR-ABL1 oncoprotein. BCR-ABL1 is the hallmark of CML in which treatment-free remission (TFR) is limited with clinical and economic consequences. Thus, there is an urgent need for novel therapeutics, which synergize with current treatment approaches. Several inhibitors targeting the N-terminal domain (NTD) of HSP90 are under investigation; however, side effects such as induction of heat shock response (HSR) and toxicity have so far precluded their FDA approval. We have developed a novel inhibitor (referred to as aminoxyrone) of HSP90 function by targeting HSP90 dimerization via the C-terminal domain (CTD). This was achieved by structure-based molecular design, chemical synthesis, and functional pre-clinical in vitro and in vivo validation using CML cell lines and patient-derived CML cells. Aminoxyrone (AX) is a promising potential candidate, which induces apoptosis in leukemic stem cells (LSCs) fraction (CD34+CD38-) as well as the leukemic bulk (CD34+CD38+) of primary CML and in TKI-resistant cells. Furthermore, BCR-ABL1 oncoprotein and related pro-oncogenic cellular responses are downregulated and targeting HSP90 C-terminus by AX does not induce HSR in vitro and in vivo. We also probed the potential of AX in other therapy refractory leukemia such as BCR-ABL1+ BCP-ALL, FLT3-ITD+ AML and Ph-like BCP-ALL. Therefore, AX is the first peptidometic C-terminal HSP90 inhibitor with the potential to increase TFR in TKI sensitive and refractory CML patients and also offers a novel therapeutic option for patients with other therapy-refractory leukemia, due to its low toxicity profile and lack of HSR.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:29724897
%U <Go to ISI:>//WOS:000439131800011
%R 10.1182/blood-2017-10-810986
%U https://juser.fz-juelich.de/record/845779