Y‐632 inhibits heat shock protein 90 (Hsp90) function by disrupting the interaction between Hsp90 and Hsp70/Hsp90 organizing protein, and exerts antitumor activity <i>in vitro</i> and <i>in vivo</i>

Wang, Wenqian; Liu, Yang; Zhao, Zhixin; Xie, Conghua; Xu, Yongping; Hu, Youhong; Quan, Hui; Lou, Liguang

doi:10.1111/cas.12934

Cited by 19 publications

(12 citation statements)

References 54 publications

(101 reference statements)

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“…For signaling protein expression changes, we found that Hsp70 was induced in all four cell lines, which is a canonical effect of this class of Hsp90 inhibitors and serves as a marker of Hsp90 inhibition (Fig. 1, A and B) (24,25). We also found that Hsp90 inhibition altered the protein expression levels of the MOR itself and of the signaling regulator ␤arr2 and the kinase Akt.…”

Section: Hsp90 Inhibition In Cell Models Of Mor Signalingmentioning

confidence: 63%

Heat-shock protein 90 (Hsp90) promotes opioid-induced anti-nociception by an ERK mitogen-activated protein kinase (MAPK) mechanism in mouse brain

Mullen

McCarthy

et al. 2017

Journal of Biological Chemistry

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Recent advances in developing opioid treatments for pain with reduced side effects have focused on the signaling cascades of the μ-opioid receptor (MOR). However, few such signaling targets have been identified for exploitation. To address this need, we explored the role of heat-shock protein 90 (Hsp90) in opioid-induced MOR signaling and pain, which has only been studied in four previous articles. First, in four cell models of MOR signaling, we found that Hsp90 inhibition for 24 h with the inhibitor 17--allylamino-17-demethoxygeldanamycin (17-AAG) had different effects on protein expression and opioid signaling in each line, suggesting that cell models may not be reliable for predicting pharmacology with this protein. We thus developed an model using CD-1 mice with an intracerebroventricular injection of 17-AAG for 24 h. We found that Hsp90 inhibition strongly blocked morphine-induced anti-nociception in models of post-surgical and HIV neuropathic pain but only slightly blocked anti-nociception in a naive tail-flick model, while enhancing morphine-induced precipitated withdrawal. Seeking a mechanism for these changes, we found that Hsp90 inhibition blocks ERK MAPK activation in the periaqueductal gray and caudal brain stem. We tested these signaling changes by inhibiting ERK in the above-mentioned pain models and found that ERK inhibition could account for all of the changes in anti-nociception induced by Hsp90 inhibition. Taken together, these findings suggest that Hsp90 promotes opioid-induced anti-nociception by an ERK mechanism in mouse brain and that Hsp90 could be a future target for improving the therapeutic index of opioid drugs.

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Section: Hsp90 Inhibition In Cell Models Of Mor Signalingmentioning

confidence: 63%

Heat-shock protein 90 (Hsp90) promotes opioid-induced anti-nociception by an ERK mitogen-activated protein kinase (MAPK) mechanism in mouse brain

Mullen

McCarthy

et al. 2017

Journal of Biological Chemistry

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“…Western blotting was carried out as described previously . In brief, cells were lysed in SDS sample buffer, then separated by SDS‐PAGE, and transferred to PVDF membranes (Millipore, Bedford, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Western blotting was carried out as described previously. (16) In brief, cells were lysed in SDS sample buffer, then separated by SDS-PAGE, and transferred to PVDF membranes (Millipore, Bedford, MA, USA). Membranes were incubated with primary antibodies at 4°C overnight and then with secondary antibodies for 2 h at room temperature.…”

Section: Methodsmentioning

confidence: 99%

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Aberrant intracellular metabolism of T‐DM1 confers T‐DM1 resistance in human epidermal growth factor receptor 2‐positive gastric cancer cells

Wang

et al. 2017

Cancer Science

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Trastuzumab emtansine (T‐DM1), an antibody–drug conjugate (ADC) consisting of human epidermal growth factor receptor 2 (HER2)‐targeted mAb trastuzumab linked to antimicrotubule agent mertansine (DM1), has been approved for the treatment of HER2‐positive metastatic breast cancer. Acquired resistance has been a major obstacle to T‐DM1 treatment, and mechanisms remain incompletely understood. In the present study, we established a T‐DM1‐resistant N87‐KR cell line from HER2‐positive N87 gastric cancer cells to investigate mechanisms of acquired resistance and develop strategies for overcoming it. Although the kinetics of binding, internalization, and externalization of T‐DM1 were the same in N87‐KR cells and N87 cells, N87‐KR was strongly resistant to T‐DM1, but remained sensitive to both trastuzumab and DM1. T‐DM1 failed to inhibit microtubule polymerization in N87‐KR cells. Consistently, lysine‐MCC‐DM1, the active T‐DM1 metabolite that inhibits microtubule polymerization, accumulated much less in N87‐KR cells than in N87 cells. Furthermore, lysosome acidification, achieved by vacuolar H+‐ATPase (V‐ATPase), was much diminished in N87‐KR cells. Notably, treatment of sensitive N87 cells with the V‐ATPase selective inhibitor bafilomycin A1 induced T‐DM1 resistance, suggesting that aberrant V‐ATPase activity decreases T‐DM1 metabolism, leading to T‐DM1 resistance in N87‐KR cells. Interestingly, HER2‐targeted ADCs containing a protease‐cleavable linker, such as hertuzumab‐vc‐monomethyl auristatin E, were capable of efficiently overcoming this resistance. Our results show for the first time that a decrease in T‐DM1 metabolites induced by aberrant V‐ATPase activity contributes to T‐DM1 resistance, which could be overcome by HER2‐targeted ADCs containing different linkers, including a protease‐cleavable linker. Accordingly, we propose that V‐ATPase activity in lysosomes is a novel biomarker for predicting T‐DM1 resistance.

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“…However, these toxoflavins are compromised in their usefulness by being ubiquitous ‘frequent hitters’ in HTS campaigns as well as very toxic to cells 40 – 43 . More recently, a structurally related chemical series of thiol-reactive acrylamide-containing compounds has also been published 44 . These compounds do not bind Hsp90 or its cochaperones, but exert their activity through intracellular thiol oxidation.…”

Section: Introductionmentioning

confidence: 99%

Solution structure of the Hop TPR2A domain and investigation of target druggability by NMR, biochemical and in silico approaches

Darby

Vidler

Simpson

et al. 2020

Sci Rep

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Heat shock protein 90 (Hsp90) is a molecular chaperone that plays an important role in tumour biology by promoting the stabilisation and activity of oncogenic ‘client’ proteins. Inhibition of Hsp90 by small-molecule drugs, acting via its ATP hydrolysis site, has shown promise as a molecularly targeted cancer therapy. Owing to the importance of Hop and other tetratricopeptide repeat (TPR)-containing cochaperones in regulating Hsp90 activity, the Hsp90-TPR domain interface is an alternative site for inhibitors, which could result in effects distinct from ATP site binders. The TPR binding site of Hsp90 cochaperones includes a shallow, positively charged groove that poses a significant challenge for druggability. Herein, we report the apo, solution-state structure of Hop TPR2A which enables this target for NMR-based screening approaches. We have designed prototype TPR ligands that mimic key native ‘carboxylate clamp’ interactions between Hsp90 and its TPR cochaperones and show that they block binding between Hop TPR2A and the Hsp90 C-terminal MEEVD peptide. We confirm direct TPR-binding of these ligands by mapping 1H–15N HSQC chemical shift perturbations to our new NMR structure. Our work provides a novel structure, a thorough assessment of druggability and robust screening approaches that may offer a potential route, albeit difficult, to address the chemically challenging nature of the Hop TPR2A target, with relevance to other TPR domain interactors.

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Y‐632 inhibits heat shock protein 90 (Hsp90) function by disrupting the interaction between Hsp90 and Hsp70/Hsp90 organizing protein, and exerts antitumor activity in vitro and in vivo

Cited by 19 publications

References 54 publications

Heat-shock protein 90 (Hsp90) promotes opioid-induced anti-nociception by an ERK mitogen-activated protein kinase (MAPK) mechanism in mouse brain

Heat-shock protein 90 (Hsp90) promotes opioid-induced anti-nociception by an ERK mitogen-activated protein kinase (MAPK) mechanism in mouse brain

Aberrant intracellular metabolism of T‐DM1 confers T‐DM1 resistance in human epidermal growth factor receptor 2‐positive gastric cancer cells

Solution structure of the Hop TPR2A domain and investigation of target druggability by NMR, biochemical and in silico approaches

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