Journal Article

FZJ-2018-02988

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Targeting HSP90 dimerization via the C-terminus is effective in imatinib resistant CML and lacks heat shock response

Bhatia, S. ; Diedrich, D. ; Frieg, B.FZJ* ; Ahlert, H. ; Stein, S. ; Bopp, B. ; Lang, F. ; Zang, T. ; Kröger, T. ; Ernst, T. ; Kögler, G. ; Krieg, A. ; Lüdeke, S. ; Kunkel, H. ; Rodrigues Moita, A. J. ; Kassack, M. U. ; Marquardt, V. ; Opitz, F. V. ; Oldenburg, M. ; Remke, M. ; Babor, F. ; Grez, M. ; Hochhaus, A. ; Borkhardt, A. ; Groth, G. ; Nagel-Steger, L.FZJ* ; Jose, J. ; Kurz, T. ; Gohlke, H.FZJ* ; Hansen, F. K. (Corresponding author) ; Hauer, J. (Corresponding author)

2018
HighWire Press Stanford, Calif.

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Please use a persistent id in citations: doi:10.1182/blood-2017-10-810986

Abstract: 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.

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Contributing Institute(s):

1. Jülich Supercomputing Center (JSC)
2. John von Neumann - Institut für Computing (NIC)
3. Strukturbiochemie (ICS-6)

Research Program(s):

1. 511 - Computational Science and Mathematical Methods (POF3-511) (POF3-511)
2. 561 - Biological Key Regulators and Small Chemical Compounds (POF3-561) (POF3-561)
3. 316 - Infections and cancer (POF3-316) (POF3-316)
4. Forschergruppe Gohlke (hkf7_20170501) (hkf7_20170501)

Appears in the scientific report 2018

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Database coverage:
; BIOSIS Previews ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 10 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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