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

Author:

Bhatia Sanil1ORCID,Diedrich Daniela2,Frieg Benedikt23ORCID,Ahlert Heinz1,Stein Stefan4,Bopp Bertan5,Lang Franziska1,Zang Tao67,Kröger Tobias2,Ernst Thomas8,Kögler Gesine9,Krieg Andreas10,Lüdeke Steffen11,Kunkel Hana4,Rodrigues Moita Ana J.2,Kassack Matthias U.2,Marquardt Viktoria121213,Opitz Friederike V.1,Oldenburg Marina1,Remke Marc11213,Babor Florian1,Grez Manuel4,Hochhaus Andreas8,Borkhardt Arndt1,Groth Georg14,Nagel-Steger Luitgard67,Jose Joachim5,Kurz Thomas2ORCID,Gohlke Holger23ORCID,Hansen Finn K.215ORCID,Hauer Julia1ORCID

Affiliation:

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

Abstract

Key Points We have developed a first-in-class C-terminal HSP90 inhibitor (AX) that is effective against TKI-resistant CML and leukemic stem cells. Unlike the majority of HSP90 inhibitors, AX does not induce the HSR as a resistance mechanism.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

Reference57 articles.

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2. Hsp90 inhibitors for the treatment of chronic myeloid leukemia;Khajapeer,2015

3. The HSP90 inhibitor ganetespib: A potential effective agent for Acute Myeloid Leukemia in combination with cytarabine;Lazenby;Leuk Res,2015

4. The therapeutic target Hsp90 and cancer hallmarks;Miyata;Curr Pharm Des,2013

5. Molecular basis for the actions of Hsp90 inhibitors and cancer therapy;Yamaki;J Antibiot (Tokyo),2011

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