2. Academic Validation
  3. Targeting HSP90 dimerization via the C terminus is effective in imatinib-resistant CML and lacks the heat shock response

Targeting HSP90 dimerization via the C terminus is effective in imatinib-resistant CML and lacks the heat shock response

  • Blood. 2018 Jul 19;132(3):307-320. doi: 10.1182/blood-2017-10-810986.
Sanil Bhatia 1,  Daniela Diedrich 2,  Benedikt Frieg 2 3,  Heinz Ahlert 1,  Stefan Stein 4,  Bertan Bopp 5,  Franziska Lang 1,  Tao Zang 6 7,  Tobias Kröger 2,  Thomas Ernst 8,  Gesine Kögler 9,  Andreas Krieg 10,  Steffen Lüdeke 11,  Hana Kunkel 4,  Ana J Rodrigues Moita 2,  Matthias U Kassack 2,  Viktoria Marquardt 1 2 12 13,  Friederike V Opitz 1,  Marina Oldenburg 1,  Marc Remke 1 12 13,  Florian Babor 1,  Manuel Grez 4,  Andreas Hochhaus 8,  Arndt Borkhardt 1,  Georg Groth 14,  Luitgard Nagel-Steger 6 7,  Joachim Jose 5,  Thomas Kurz 2,  Holger Gohlke 2 3,  Finn K Hansen 2 15,  Julia Hauer 1
Affiliations

Affiliations

  • 1 Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, and.
  • 2 Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
  • 3 John von Neumann Institute for Computing, Jülich Supercomputing Centre, Institute for Complex Systems-Structural Biochemistry (ICS-6), Forschungszentrum Jülich GmbH, Jülich, Germany.
  • 4 Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany.
  • 5 Institute for Pharmaceutical and Medicinal Chemistry, PharmaCampus, Westphalian Wilhelms University, Münster, Germany.
  • 6 Institute for Physical Biology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
  • 7 Institute of Complex Systems, Structural Biochemistry (ICS-6), Forschungszentrum Jülich GmbH, Jülich, Germany.
  • 8 Hematology/Oncology, Internal Medicine II, Jena University Hospital, Jena, Germany.
  • 9 Institute for Transplantation Diagnostics and Cell Therapeutics and.
  • 10 Department of Surgery (A), Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
  • 11 Institute of Pharmaceutical Sciences, University of Freiburg, Freiburg, Germany.
  • 12 Institute of Neuropathology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
  • 13 Division of Pediatric Neuro-Oncogenomics, German Cancer Consortium, partner site University Hospital Düsseldorf, Düsseldorf, Germany.
  • 14 Institute for Biochemical Plant Physiology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; and.
  • 15 Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Leipzig University, Leipzig, Germany.
PMID: 29724897 DOI: 10.1182/blood-2017-10-810986
Abstract

Heat shock protein 90 (HSP90) stabilizes many client proteins, including the BCR-ABL1 oncoprotein. BCR-ABL1 is the hallmark of chronic myeloid leukemia (CML) in which treatment-free remission (TFR) is limited, with clinical and economic consequences. Thus, there is an urgent need for novel therapeutics that synergize with current treatment approaches. Several inhibitors targeting the N-terminal domain of HSP90 are under investigation, but side effects such as induction of the heat shock response (HSR) and toxicity have so far precluded their US Food and Drug Administration approval. We have developed a novel inhibitor (aminoxyrone [AX]) of HSP90 function by targeting HSP90 dimerization via the C-terminal domain. This was achieved by structure-based molecular design, chemical synthesis, and functional preclinical in vitro and in vivo validation using CML cell lines and patient-derived CML cells. AX is a promising potential candidate that induces Apoptosis in the leukemic stem cell fraction (CD34+CD38-) as well as the leukemic bulk (CD34+CD38+) of primary CML and in tyrosine kinase inhibitor (TKI)-resistant cells. Furthermore, BCR-ABL1 oncoprotein and related pro-oncogenic cellular responses are downregulated, and targeting the HSP90 C terminus by AX does not induce the HSR in vitro and in vivo. We also probed the potential of AX in Other therapy-refractory leukemias. Therefore, AX is the first peptidomimetic 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 types of therapy-refractory leukemia because of its low toxicity profile and lack of HSR.

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