TY  - JOUR
AU  - Bhatia, Sanil
AU  - Diedrich, Daniela
AU  - Frieg, Benedikt
AU  - Ahlert, Heinz
AU  - Stein, Stefan
AU  - Bopp, Bertan
AU  - Lang, Franziska
AU  - Zang, Tao
AU  - Kröger, Tobias
AU  - Ernst, Thomas
AU  - Kögler, Gesine
AU  - Krieg, Andreas
AU  - Lüdeke, Steffen
AU  - Kunkel, Hana
AU  - Rodrigues Moita, Ana J.
AU  - Kassack, Matthias U.
AU  - Marquardt, Viktoria
AU  - Opitz, Friederike V.
AU  - Oldenburg, Marina
AU  - Remke, Marc
AU  - Babor, Florian
AU  - Grez, Manuel
AU  - Hochhaus, Andreas
AU  - Borkhardt, Arndt
AU  - Groth, Georg
AU  - Nagel-Steger, Luitgard
AU  - Jose, Joachim
AU  - Kurz, Thomas
AU  - Gohlke, Holger
AU  - Hansen, Finn K.
AU  - Hauer, Julia
TI  - Targeting HSP90 dimerization via the C-terminus is effective in imatinib resistant CML and lacks heat shock response
JO  - Blood
VL  - 132
IS  - 3
SN  - 1528-0020
CY  - Stanford, Calif.
PB  - HighWire Press
M1  - FZJ-2018-02988
SP  - 307-320
PY  - 2018
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:29724897
UR  - <Go to ISI:>//WOS:000439131800011
DO  - DOI:10.1182/blood-2017-10-810986
UR  - https://juser.fz-juelich.de/record/845779
ER  -