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

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 (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.

Quantitative assessment of the determinant structural differences between redox-active and inactive glutaredoxins

“…The MEP was calculated on four layers defined by scaling the atomic van der Waals radii by factors of 1.4, 1.8, 2.0, and 2.2, respectively, and a point density of 0.28 points au −2 (1 pt Å −2 ). Charge fitting was performed using the RESP procedure with two fitting stages (hyperbolic constraint values: 0.0005/0.001), and intramolecular charge constraints on the N-methylamide fragment of γ glutamylmethylamide with a target value of zero were employed for charge derivation 71,72 . Lastly, the charge constrained atoms were removed to obtain the γ-glutamyl residue.…”

“…The system state was saved every 20 ps. This setup allowed us to observe the unbiased diffusion 72,75 of GS − around the Grx proteins. Binding frequencies were calculated as the fraction of frames with a binding event of all the frames per simulation replication.…”

Harnessing host–virus evolution in antiviral therapy and immunotherapy

“…Accordingly, HSP90 inhibitors 17‐AAG/tanespimycin and AUY922 (Table ) were recently shown to inhibit HIV‐1 transcription and suppress viral rebound in a humanised mouse model . Although these and other HSP90 inhibitors have encountered efficacy and toxicity issues during clinical trials as anticancer therapies, aminoxyrone is novel, first‐in‐class HSP90 inhibitor that appears to alleviate both issues . Its efficacy as an antiviral or antiretroviral therapeutic has yet to be studied.…”

“…In addition to impairing HIV‐1 replication, HSP90 inhibitors reportedly inhibit IAV replication without apparent cytotoxicity in vitro . It will be of interest to examine whether these effects translate in vivo using next‐generation HSP90 inhibitors (Table ).…”

Neferine in the Lotus Plumule Potentiates the Antitumor Effect of Imatinib in Primary Chronic Myeloid Leukemia Cells In Vitro

“…When compared to normal cells, the expression of Hsp90 is increased in solid tumors and hematological malignancies (Augello et al., ; Coskunpinar et al., ; Yufu, Nishimura, & Nawata, ). Elevated Hsp90 levels protect BCR‐ABL by inhibiting its degradation, whereas Hsp90 inhibitors block the binding of BCR‐ABL and Hsp90, resulting in BCR‐ABL degradation via the proteasome pathway, thereby overcoming imatinib‐resistance of CML cells bearing a BCR‐ABL‐T315I mutation (An, Schulte, & Neckers, ; Bhatia et al., ; Lu, Jin, Qiu, Lai, & Pan, ). In addition, BCR‐ABL activated a number of signal transduction pathways and genes involved in malignant hematopoietic cell growth that prevent apoptosis, including JAK/STAT, Raf/MEK/Erk, PI3K/Akt, BCL‐XL, BCL‐2, and Mcl‐1 (Aichberger et al., ; Amarante‐Mendes et al., ; Steelman et al., ).…”