The Development of Hsp90β-Selective Inhibitors to Overcome Detriments Associated with <i>pan</i>-Hsp90 Inhibition

Mishra, Satyendra; Liu, Weiya; Beebe, Kristin; Banerjee, Monimoy; Kent, Caitlin N.; Munthali, Vitumbiko; Koren, John; Taylor, John A.; Neckers, Leonard Μ.; Holzbeierlein, Jeffrey M.; Blagg, Brian S. J.

doi:10.1021/acs.jmedchem.0c01700

Cited by 42 publications

(42 citation statements)

References 43 publications

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“…More than 20 inhibitors of Hsp90 have entered clinical trials for cancer treatment, however most of them encountered deleterious side effects and toxicities [19]. The wide spectrum inhibitory effect of HSP90 inhibitors on the client proteins is one of the primary causes for the failure of these inhibitors in the clinical trials [20]. Intriguingly, AHSA1 selectively mediates the recruitment of client proteins to Hsp90 system as an adaptor co-chaperone suggesting the therapeutic potential of targeting AHSA1 in cancer treatment [18,21,22].…”

Section: Introductionmentioning

confidence: 99%

AHSA1 is a promising therapeutic target for cellular proliferation and proteasome inhibitor resistance in multiple myeloma

Wang

Zhang

et al. 2022

J Exp Clin Cancer Res

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Background Currently, multiple myeloma (MM) is still an incurable plasma cell malignancy in urgent need of novel therapeutic targets and drugs. Methods Bufalin was known as a highly toxic but effective anti-cancer compound. We used Bufalin as a probe to screen its potential targets by proteome microarray, in which AHSA1 was the unique target of Bufalin. The effects of AHSA1 on cellular proliferation and drug resistance were determined by MTT, western blot, flow cytometry, immunohistochemistry staining and xenograft model in vivo. The potential mechanisms of Bufalin and KU-177 in AHSA1/HSP90 were verified by co-immunoprecipitation, mass spectrometry, site mutation and microscale thermophoresis assay. Results AHSA1 expression was increased in MM samples compared to normal controls, which was significantly associated with MM relapse and poor outcomes. Furthermore, AHSA1 promoted MM cell proliferation and proteasome inhibitor (PI) resistance in vitro and in vivo. Mechanism exploration indicated that AHSA1 acted as a co-chaperone of HSP90A to activate CDK6 and PSMD2, which were key regulators of MM proliferation and PI resistance respectively. Additionally, we identified AHSA1-K137 as the specific binding site of Bufalin on AHSA1, mutation of which decreased the interaction of AHSA1 with HSP90A and suppressed the function of AHSA1 on mediating CDK6 and PSMD2. Intriguingly, we discovered KU-177, an AHSA1 selective inhibitor, and found KU-177 targeting the same site as Bufalin. Bufalin and KU-177 treatments hampered the proliferation of flow MRD-positive cells in both primary MM and recurrent MM patient samples. Moreover, KU-177 abrogated the cellular proliferation and PI resistance induced by elevated AHSA1, and decreased the expression of CDK6 and PSMD2. Conclusions We demonstrate that AHSA1 may serve as a promising therapeutic target for cellular proliferation and proteasome inhibitor resistance in multiple myeloma.

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Section: Introductionmentioning

confidence: 99%

AHSA1 is a promising therapeutic target for cellular proliferation and proteasome inhibitor resistance in multiple myeloma

Wang

Zhang

et al. 2022

J Exp Clin Cancer Res

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“…Cytotoxicity was evaluated using the neutral red assay as described previously (Mishra et al, 2021). Briefly, 300,000 cells were seeded in supplemented Dulbecco´s Modified Eagle´s Medium (DMEM) medium as described above to 96-well plates.…”

Section: Cytotoxicity Assaymentioning

confidence: 99%

Boromycin has Rapid-Onset Antibiotic Activity Against Asexual and Sexual Blood Stages of Plasmodium falciparum

Carvalho

Groeger-Otero

Kreidenweiss

et al. 2022

Front. Cell. Infect. Microbiol.

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Boromycin is a boron-containing macrolide antibiotic produced by Streptomyces antibioticus with potent activity against certain viruses, Gram-positive bacteria and protozoan parasites. Most antimalarial antibiotics affect plasmodial organelles of prokaryotic origin and have a relatively slow onset of action. They are used for malaria prophylaxis and for the treatment of malaria when combined to a fast-acting drug. Despite the success of artemisinin combination therapies, the current gold standard treatment, new alternatives are constantly needed due to the ability of malaria parasites to become resistant to almost all drugs that are in heavy clinical use. In vitro antiplasmodial activity screens of tetracyclines (omadacycline, sarecycline, methacycline, demeclocycline, lymecycline, meclocycline), macrolides (oleandomycin, boromycin, josamycin, troleandomycin), and control drugs (chloroquine, clindamycin, doxycycline, minocycline, eravacycline) revealed boromycin as highly potent against Plasmodium falciparum and the zoonotic Plasmodium knowlesi. In contrast to tetracyclines, boromycin rapidly killed asexual stages of both Plasmodium species already at low concentrations (~ 1 nM) including multidrug resistant P. falciparum strains (Dd2, K1, 7G8). In addition, boromycin was active against P. falciparum stage V gametocytes at a low nanomolar range (IC50: 8.5 ± 3.6 nM). Assessment of the mode of action excluded the apicoplast as the main target. Although there was an ionophoric activity on potassium channels, the effect was too low to explain the drug´s antiplasmodial activity. Boromycin is a promising antimalarial candidate with activity against multiple life cycle stages of the parasite.

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“…For this purpose, Hsp90 undergoes a plethora of transient interactions [103] with assisting cochaperones and diverse client proteins including regulatory kinases, hormone receptors, and transcription factors, such as the tumor suppressor p53, making it a central drug target for anti-cancer therapy [104,105]. Despite its biomedical importance and the related intense research activity over the past decades [106][107][108], even fundamental functional aspects have remained enigmatic, such as the role of Hsp90's notoriously slow ATPase function for the chaperoning action [109]. Two recent cryoEM structures provide an unprecedent molecular view on the intricate multipartite complexes involved in client loading and maturation of the steroid hormone receptor GR by Hsp90 [110,111], however the dynamic time-domain information on client processing lags once more behind its 3D structural counterpart.…”

Section: Hsp90 'Chaperones' the Proteomementioning

confidence: 99%

Can DyeCycling break the photobleaching limit in single-molecule FRET?

Vermeer

Schmid

2022

Preprint

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Biomolecular systems, such as proteins, crucially rely on dynamic processes at the nanoscale. Detecting biomolecular nanodynamics is therefore key to obtaining a mechanistic understanding of the energies and molecular driving forces that control biomolecular systems. Single-molecule fluorescence resonance energy transfer (smFRET) is a powerful technique to observe in real-time how a single biomolecule proceeds through its functional cycle involving a sequence of distinct structural states. Currently, this technique is fundamentally limited by irreversible photobleaching, causing the untimely end of the experiment and thus, a prohibitively narrow temporal bandwidth of ≤ 3 orders of magnitude. Here, we introduce ″DyeCycling″, a measurement scheme with which we aim to break the photobleaching limit in single-molecule FRET. We introduce the concept of spontaneous dye replacement by simulations, and as an experimental proof-of-concept, we demonstrate the intermittent observation of a single biomolecule for one hour with a time resolution of milliseconds. Theoretically, DyeCycling can provide >100-fold more information per single molecule than conventional smFRET. We discuss the experimental implementation of DyeCycling, its current and fundamental limitations, and specific biological use cases. Given its general simplicity and versatility, DyeCycling has the potential to revolutionize the field of time-resolved smFRET, where it may serve to unravel a wealth of biomolecular dynamics by bridging from milliseconds to the hour range.

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The Development of Hsp90β-Selective Inhibitors to Overcome Detriments Associated with pan-Hsp90 Inhibition

Cited by 42 publications

References 43 publications

AHSA1 is a promising therapeutic target for cellular proliferation and proteasome inhibitor resistance in multiple myeloma

AHSA1 is a promising therapeutic target for cellular proliferation and proteasome inhibitor resistance in multiple myeloma

Boromycin has Rapid-Onset Antibiotic Activity Against Asexual and Sexual Blood Stages of Plasmodium falciparum

Can DyeCycling break the photobleaching limit in single-molecule FRET?

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