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@ARTICLE{Bhatia:845779,
      author       = {Bhatia, Sanil and Diedrich, Daniela and Frieg, Benedikt and
                      Ahlert, Heinz and Stein, Stefan and Bopp, Bertan and Lang,
                      Franziska and Zang, Tao and Kröger, Tobias and Ernst,
                      Thomas and Kögler, Gesine and Krieg, Andreas and Lüdeke,
                      Steffen and Kunkel, Hana and Rodrigues Moita, Ana J. and
                      Kassack, Matthias U. and Marquardt, Viktoria and Opitz,
                      Friederike V. and Oldenburg, Marina and Remke, Marc and
                      Babor, Florian and Grez, Manuel and Hochhaus, Andreas and
                      Borkhardt, Arndt and Groth, Georg and Nagel-Steger, Luitgard
                      and Jose, Joachim and Kurz, Thomas and Gohlke, Holger and
                      Hansen, Finn K. and Hauer, Julia},
      title        = {{T}argeting {HSP}90 dimerization via the {C}-terminus is
                      effective in imatinib resistant {CML} and lacks heat shock
                      response},
      journal      = {Blood},
      volume       = {132},
      number       = {3},
      issn         = {1528-0020},
      address      = {Stanford, Calif.},
      publisher    = {HighWire Press},
      reportid     = {FZJ-2018-02988},
      pages        = {307-320},
      year         = {2018},
      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.},
      cin          = {JSC / NIC / ICS-6},
      ddc          = {610},
      cid          = {I:(DE-Juel1)JSC-20090406 / I:(DE-Juel1)NIC-20090406 /
                      I:(DE-Juel1)ICS-6-20110106},
      pnm          = {511 - Computational Science and Mathematical Methods
                      (POF3-511) / 561 - Biological Key Regulators and Small
                      Chemical Compounds (POF3-561) / 316 - Infections and cancer
                      (POF3-316) / Forschergruppe Gohlke $(hkf7_20170501)$},
      pid          = {G:(DE-HGF)POF3-511 / G:(DE-HGF)POF3-561 /
                      G:(DE-HGF)POF3-316 / $G:(DE-Juel1)hkf7_20170501$},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29724897},
      UT           = {WOS:000439131800011},
      doi          = {10.1182/blood-2017-10-810986},
      url          = {https://juser.fz-juelich.de/record/845779},
}