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• The 90 kDa heat shock protein (HSP90) is widely involved in various developmental processes and stress responses in plants. However, the molecular chaperone HSP90-constructed protein complex and its function in cassava remain elusive. • In this study, we report that HSP90 is essential for drought stress resistance in cassava by regulating abscisic acid (ABA) and hydrogen peroxide (H₂O₂) using two specific protein inhibitors of HSP90 (geldanamycin (GDA) and radicicol (RAD)). Among 10 MeHSP90s, the transcript of MeHSP90.9 is largely induced during drought stress. Further investigation identifies MeWRKY20 and MeCatalase1 as MeHSP90.9-interacting proteins. MeHSP90.9-, MeWRKY20-, or MeCatalase1-silenced plants through virus-induced gene silencing display drought sensitivity in cassava, indicating that they are important to drought stress response. • MeHSP90.9 can promote the direct transcriptional activation of MeWRKY20 on the W-box element of MeNCED5 promoter, encoding a key enzyme in ABA biosynthesis. Moreover, MeHSP90.9 positively regulates the activity of MeCatalase1, and MeHSP90.9-silenced cassava leaves accumulate more H₂O₂ under drought stress. • Taken together, we demonstrate that the MeHSP90.9 chaperone complex is a regulator of drought stress resistance in cassava.

Once activated, the intracellular receptor NLRP3 assembles an inflammasome protein complex that facilitates the caspase-1-mediated maturation of IL-1β and IL-18. Inactive NLRP3 is guarded by a protein complex containing Hsp90. In response to stress stimuli, Hsp90 is released, and NLRP3 can be activated to promote inflammation. In this study, we blocked Hsp90 with geldanamycin and studied the fate of NLRP3 in human retinal pigment epithelial (RPE) cells. RPE cells play a central role in the development of age-related macular degeneration (AMD), a progressive eye disease causing severe vision loss in the elderly. IL-1α-primed ARPE-19 cells, human embryonal stem cell (hESC)-derived RPE cells, and primary human RPE cells were exposed to MG-132 and bafilomycin A to activate NLRP3 via the inhibition of proteasomes and autophagy, respectively. Additionally, RPE cells were treated with geldanamycin at different time points and the levels of NLRP3 and IL-1β were determined. Caspase-1 activity was measured using a commercial assay. Geldanamycin prevented the activation of the inflammasome in human RPE cells. NLRP3 released from its protective complex became degraded by autophagy or secreted from the cells. Controlled destruction of NLRP3 is a potential way to regulate the inflammation associated with chronic diseases, such as AMD.

The transcription factor, forkhead box M1 (FOXM1), has been implicated in the natural history and outcome of newly diagnosed high-risk myeloma (HRMM) and relapsed/refractory myeloma (RRMM), but the mechanism with which FOXM1 promotes the growth of neoplastic plasma cells is poorly understood. Here we show that FOXM1 is a positive regulator of myeloma metabolism that greatly impacts the bioenergetic pathways of glycolysis and oxidative phosphorylation (OxPhos). Using FOXM1-deficient myeloma cells as principal experimental model system, we find that FOXM1 increases glucose uptake, lactate output, and oxygen consumption in myeloma. We demonstrate that the novel 1,1-diarylethylene small-compound FOXM1 inhibitor, NB73, suppresses myeloma in cell culture and human-in-mouse xenografts using a mechanism that includes enhanced proteasomal FOXM1 degradation. Consistent with the FOXM1-stabilizing chaperone function of heat shock protein 90 (HSP90), the HSP90 inhibitor, geldanamycin, collaborates with NB73 in slowing down myeloma. These findings define FOXM1 as a key driver of myeloma metabolism and underscore the feasibility of targeting FOXM1 for new approaches to myeloma therapy and prevention.

Goblet cell metaplasia, a disabling hallmark of chronic lung disease, lacks curative treatments at present. To identify novel therapeutic targets for goblet cell metaplasia, we studied the transcriptional response profile of IL-13-exposed primary human airway epithelia in vitro and asthmatic airway epithelia in vivo. A perturbation-response profile connectivity approach identified geldanamycin, an inhibitor of heat shock protein 90 (HSP90) as a candidate therapeutic target. Our experiments confirmed that geldanamycin and other HSP90 inhibitors prevented IL-13-induced goblet cell metaplasia in vitro and in vivo. Geldanamycin also reverted established goblet cell metaplasia. Geldanamycin did not induce goblet cell death, nor did it solely block mucin synthesis or IL-13 receptor-proximal signaling. Geldanamycin affected the transcriptome of airway cells when exposed to IL-13, but not when exposed to vehicle. We hypothesized that the mechanism of action probably involves TGF-β, ERBB, or EHF, which would predict that geldanamycin would also revert IL-17-induced goblet cell metaplasia, a prediction confirmed by our experiments. Our findings suggest that persistent airway goblet cell metaplasia requires HSP90 activity and that HSP90 inhibitors will revert goblet cell metaplasia, despite active upstream inflammatory signaling. Moreover, HSP90 inhibitors may be a therapeutic option for airway diseases with goblet cell metaplasia of unknown mechanism.

Heat shock protein (HSP90), a highly conserved molecular chaperon, is indispensable for the maturation of newly synthesized poly-peptides and provides a shelter for the turnover of misfolded or denatured proteins. In cancers, the client proteins of HSP90 extend to the entire process of oncogenesis that are associated with all hallmarks of cancer. Accumulating evidence has demonstrated that the client proteins are guided for proteasomal degradation when their complexes with HSP90 are disrupted. Accordingly, HSP90 and its co-chaperones have emerged as viable targets for the development of cancer therapeutics. Consequently, a number of natural products and their analogs targeting HSP90 have been identified. They have shown a strong inhibitory effect on various cancer types through different mechanisms. The inhibitors act by directly binding to either HSP90 or its co-chaperones/client proteins. Several HSP90 inhibitors—such as geldanamycin and its derivatives, gamitrinib and shepherdin—are under clinical evaluation with promising results. Here, we review the subcellular localization of HSP90, its corresponding mechanism of action in the malignant phenotypes, and the recent progress on the development of HSP90 inhibitors. Hopefully, this comprehensive review will shed light on the translational potential of HSP90 inhibitors as novel cancer therapeutics.

COVID-19 is a critical pandemic that has affected human communities worldwide, and there is an urgent need to develop effective drugs. Although there are a large number of candidate drug compounds that may be useful for treating COVID-19, the evaluation of these drugs is time-consuming and costly. Thus, screening to identify potentially effective drugs prior to experimental validation is necessary. In this study, we applied the recently proposed method tensor decomposition (TD)-based unsupervised feature extraction (FE) to gene expression profiles of multiple lung cancer cell lines infected with severe acute respiratory syndrome coronavirus 2. We identified drug candidate compounds that significantly altered the expression of the 163 genes selected by TD-based unsupervised FE. Numerous drugs were successfully screened, including many known antiviral drug compounds such as C646, chelerythrine chloride, canertinib, BX-795, sorafenib, sorafenib, QL-X-138, radicicol, A-443654, CGP-60474, alvocidib, mitoxantrone, QL-XII-47, geldanamycin, fluticasone, atorvastatin, quercetin, motexafin gadolinium, trovafloxacin, doxycycline, meloxicam, gentamicin, and dibromochloromethane. The screen also identified ivermectin, which was first identified as an anti-parasite drug and recently the drug was included in clinical trials for SARS-CoV-2. The drugs screened using our strategy may be effective candidates for treating patients with COVID-19.

α-Glucosidase (AGS) inhibitors have been regarded as an ideal target for the management of type 2 diabetes mellitus (T2DM) since they can maintain an acceptable blood glucose level by delaying the digestion of carbohydrates and diminishing the absorption of monosaccharides. In the process of our endeavor in mining AGS inhibitors from natural sources, the culture broth of two mangrove-derived actinomycetes Streptomyces sp. WHUA03267 and Streptomyces sp. WHUA03072 exhibited an apparent inhibitory activity against AGS. A subsequent chemical investigation into the two extracts furnished 28 secondary metabolites that were identified by spectroscopic methods as two previously undescribed linear polyketides 1–2, four benzenoid ansamycins 3–6, fourteen cyclodipeptides 7–18, one prenylated indole derivative 19, two fusicoccane-type diterpenoids 20–21, two hydroxamate siderophore 22–23, and five others 24–28. Among all of the isolates, 11 and 24 were obtained from actinomycetes for the first time, while 20–21 had never been reported to occur in a marine-derived microorganism previously. In the in vitro AGS inhibitory assay, compounds 3, 8, 9, 11, 14, 16, and 17 exhibited potent to moderate activity with IC50 values ranging from 35.76 ± 0.40 to 164.5 ± 15.5 μM, as compared with acarbose (IC50 = 422.3 ± 8.4 μM). The AGS inhibitory activity of 3, 9, 14, 16, and 17 was reported for the first time. In particular, autolytimycin (3) represented the first ansamycin derivative reported to possess the AGS inhibitory activity. Kinetics analysis and molecular docking were performed to determine the inhibition types and binding modes of these inhibitors, respectively. In the MTT assay, 3, 8, 9, 11, 14, 16, and 17 exhibited no apparent cytotoxicity to the human normal hepatocyte (LO2) cells, suggesting satisfactory safety of these AGS inhibitors.

Quinones can in principle be viewed as a double-edged sword in the treatment of neurodegenerative diseases, since they are often cytoprotective but can also be cytotoxic due to covalent and redox modification of biomolecules. Nevertheless, low doses of moderately electrophilic quinones are generally cytoprotective, mainly due to their ability to activate the Keap1/Nrf2 pathway and thus induce the expression of detoxifying enzymes. Some natural quinones have relevant roles in important physiological processes. One of them is coenzyme Q10, which takes part in the oxidative phosphorylation processes involved in cell energy production, as a proton and electron carrier in the mitochondrial respiratory chain, and shows neuroprotective effects relevant to Alzheimer’s and Parkinson’s diseases. Additional neuroprotective quinones that can be regarded as coenzyme Q10 analogues are idobenone, mitoquinone and plastoquinone. Other endogenous quinones with neuroprotective activities include tocopherol-derived quinones, most notably vatiquinone, and vitamin K. A final group of non-endogenous quinones with neuroprotective activity is discussed, comprising embelin, APX-3330, cannabinoid-derived quinones, asterriquinones and other indolylquinones, pyrroloquinolinequinone and its analogues, geldanamycin and its analogues, rifampicin quinone, memoquin and a number of hybrid structures combining quinones with amino acids, cholinesterase inhibitors and non-steroidal anti-inflammatory drugs.

Amide synthases catalyze the formation of macrolactam rings from aniline-containing polyketide-derived seco-acids as found in the important class of ansamycin antibiotics. One of these amide synthases is the geldanamycin amide synthase GdmF, which we recombinantly expressed, purified and studied in detail both functionally as well as structurally. Here we show that purified GdmF catalyzes the amide formation using synthetically derived substrates. The atomic structures of the ligand-free enzyme and in complex with simplified substrates reveal distinct structural features of the substrate binding site and a putative role of the flexible interdomain region for the catalysis reaction. Amide synthases catalyse the formation of macrolactam rings from aniline-containing polyketide-derived seco -acids. In this study, the authors solved the crystal structure of the geldanamycin amide synthase GdmF and demonstrated that it catalyses amide formation using synthetically derived substrates.

The influence of base type, temperature, and solvent on regioselective C(9)/C(10) \"click\" modifications within the tropolone ring of colchiceine (2) is investigated. New ether derivatives of 2, bearing alkyne, azide, vinyl, or halide aryl groups enable assembly of the alkaloid part with heterocycles or important biomolecules such as saccharides, geldanamycin or AZT into hybrid scaffolds by dipolar cycloaddition (CuAAC) or Heck reaction. Compared to colchicine (1) or colchiceine (2), ether congeners, as e.g. 3e [IC 50 s ( 3e) ∼ 0.9 nM], show improved or similar anticancer effects, whereby the bulkiness of the substituents and the substitution pattern of the tropolone proved to be essential. Biological studies reveal that expanding the ether arms by terminal basic heterocycles as quinoline or pyridine, decreases the toxicity in HDF cells at high anticancer potency (IC 50 s ∼ 1-2 nM). Docking of ether and hybrid derivatives into the colchicine pocket of α GTP /β tubulin dimers reveals a relationship between the favourable binding mode and the attractive anticancer potency.