Blood, 19 July 2018, Vol.132(3), pp.307-320
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 (CD34CD38) as well as the leukemic bulk (CD34CD38) 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.
Animals–Chemistry ; Antineoplastic Agents–Pharmacology ; Binding Sites–Drug Effects ; Biomarkers, Tumor–Drug Effects ; Cell Cycle–Drug Effects ; Cell Line, Tumor–Antagonists & Inhibitors ; Cell Survival–Chemistry ; Disease Models, Animal–Antagonists & Inhibitors ; Drug Resistance, Neoplasm–Chemistry ; Fusion Proteins, Bcr-Abl–Metabolism ; Hsp90 Heat-Shock Proteins–Drug Effects ; Heat-Shock Response–Chemistry ; Humans–Pharmacology ; Imatinib Mesylate–Drug Therapy ; Leukemia, Myelogenous, Chronic, BCR-Abl Positive–Metabolism ; Mice–Chemistry ; Models, Molecular–Pharmacology ; Molecular Conformation–Drug Effects ; Molecular Structure–Drug Effects ; Protein Binding–Drug Effects ; Protein Interaction Domains and Motifs–Drug Effects ; Protein Kinase Inhibitors–Drug Effects ; Protein Multimerization–Drug Effects ; Spectrum Analysis–Drug Effects ; Structure-Activity Relationship–Drug Effects ; Xenograft Model Antitumor Assays–Drug Effects ; Abridged ; Antineoplastic Agents ; Biomarkers, Tumor ; Hsp90 Heat-Shock Proteins ; Protein Kinase Inhibitors ; Imatinib Mesylate ; Fusion Proteins, Bcr-Abl;
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