Targeting HSP90 dimerization via the C terminus is effective in imatinib-resistant CML and lacks the heat shock response
| Autor: | Finn K. Hansen, Daniela Diedrich, Joachim Jose, Viktoria Marquardt, Friederike V. Opitz, Arndt Borkhardt, Hana Kunkel, Matthias U. Kassack, Luitgard Nagel-Steger, Florian Babor, Manuel Grez, Heinz Ahlert, Thomas Kurz, Stefan Stein, Ana J. Rodrigues Moita, Tobias Kröger, Sanil Bhatia, Steffen Lüdeke, Marina Oldenburg, Holger Gohlke, Bertan Bopp, Gesine Kögler, Andreas Hochhaus, Marc Remke, Franziska Lang, Julia Hauer, Andreas Krieg, Benedikt Frieg, Tao Zang, Georg Groth, Thomas Ernst |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Models Molecular Fusion Proteins bcr-abl Molecular Conformation CD38 Biochemistry Tyrosine-kinase inhibitor Hsp90 inhibitor Mice 0302 clinical medicine hemic and lymphatic diseases Myeloid Neoplasia Molecular Structure Chemistry Cell Cycle Myeloid leukemia Hematology Leukemia 030220 oncology & carcinogenesis Imatinib Mesylate Dimerization BLOOD Commentary Protein Binding medicine.drug_class Cell Survival Immunology Antineoplastic Agents 03 medical and health sciences Structure-Activity Relationship Heat shock protein Cell Line Tumor Leukemia Myelogenous Chronic BCR-ABL Positive medicine Biomarkers Tumor Animals Humans Protein Interaction Domains and Motifs HSP90 Heat-Shock Proteins Heat shock Protein Kinase Inhibitors Binding Sites Spectrum Analysis Cell Biology medicine.disease Xenograft Model Antitumor Assays Disease Models Animal 030104 developmental biology Imatinib mesylate Drug Resistance Neoplasm Cancer research Protein Multimerization Heat-Shock Response |
| Zdroj: | Blood. 132(3) |
| ISSN: | 1528-0020 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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