Identification of Limonol Derivatives as Heat Shock Protein 90 (Hsp90) Inhibitors through a Multidisciplinary Approach

Chini, Maria Giovanna; Malafronte, Nicola; Vaccaro, Maria Carmela; Gualtieri, María; Vassallo, Antonio; Vasaturo, Michele; Castellano, Sabrina; Milite, Ciro; Leone, Antonietta; Bifulco, Giuseppe; Tommasi, Nunziatina De; Piaz, Fabrizio Dal

doi:10.1002/chem.201602242

Cited by 34 publications

(55 citation statements)

References 65 publications

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“…To evaluate the stability of the complexes between JMJD3 and compounds 3 – 12 obtained by docking analysis, we performed molecular dynamics simulations (50 ns, 310 K; see experimental details in the Supporting Information) . The trajectory analysis revealed that 3 gives a high number of contacts with protein residues, and it maintains most of the contacts observed from the docked pose during the entire simulation (>50 %) with both protein models (Figure , bottom).…”

Section: Methodsmentioning

confidence: 99%

Virtual Fragment Screening Identification of a Quinoline‐5,8‐dicarboxylic Acid Derivative as a Selective JMJD3 Inhibitor

et al. 2018

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The quinoline‐5,8 dicarboxylic acid scaffold has been identified by a fragment‐based approach as new potential lead compound for the development of JMJD3 inhibitors. Among them, 3‐(2,4‐dimethoxypyrimidin‐5‐yl)quinoline‐5,8‐dicarboxylic acid (compound 3) shows low micromolar inhibitory activity against Jumonji domain‐containing protein 3 (JMJD3). The experimental evaluation of inhibitory activity against seven related isoforms of JMJD3 highlighted an unprecedented selectivity toward the biological target of interest.

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Section: Methodsmentioning

confidence: 99%

Virtual Fragment Screening Identification of a Quinoline‐5,8‐dicarboxylic Acid Derivative as a Selective JMJD3 Inhibitor

et al. 2018

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“…Among these factors, oxidative stress may cause an imbalance between reactive oxygen species and the anti-oxidant system, which has an important role in the secondary injury component of SCI ( 6 ). Prevention of oxidative stress to reduce the degree of secondary injury has become a potential strategy for the treatment of SCI ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

Effects of ginsenoside Rb1 on oxidative stress injury in rat spinal cords by regulating the eNOS/Nrf2/HO‑1 signaling pathway

et al. 2018

Exp Ther Med

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The present study aimed to investigate whether ginsenoside Rb1 (G-Rb1) attenuates spinal cord injury-associated oxidative stress in rats by regulating the endothelial nitric oxide synthase eNOS/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase (HO)-1 signaling pathway. Sprague Dawley rats were randomly divided into the sham operation group (S group), spinal cord injury group (SCI group), G-Rb1 treatment group (G-Rb1 group) and SCI+G-Rb1+Inhibitor L-name group (L-name group). The posterior limb function was evaluated via the Basso, Beattie and Bresnahan scoring method. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT) and glutathione (GSH) in serum were measured by ELISA. The pathological changes in the spinal cord were observed by H&E staining. Reverse transcription-quantitative polymerase chain reaction and western blot analyses were used to detect eNOS, phosphorylated (p)-eNOS, heat shock protein (HSP)90, Nrf2 and NAD(P)H quinone dehydrogenase 1 (Nqo1) at the mRNA and protein level. Immunohistochemistry was used to detect the expression of Nrf2 and p-eNOS. Compared with the S group, the scores of spinal cord function in the SCI group were significantly lower, and the levels of MDA were significantly increased, while the levels of SOD, CAT and GSH protein in spinal cord were significantly decreased (P<0.05). The spinal cord tissue exhibited hemorrhage, neuronal degeneration/necrosis, as well as mononuclear cell and lymphocyte infiltration. The eNOS, HSP90, Nrf2, Nqo1 and HO-1 mRNA levels were decreased (P<0.05). Compared with those in the SCI group, the spinal cord function score in the G-Rb1 group were significantly higher and the serum MDA content was significantly decreased, while the activity of SOD, CAT and GSH was significantly increased (P<0.05). The degeneration/necrosis of spinal cord neurons was attenuated, inflammatory cell infiltration was significantly reduced and the levels of eNOS, HSP90, Nrf2, Nqo1 and HO-1 were significantly upregulated (P<0.05). In the group that was administered the eNOS inhibitor L-name, the levels of eNOS, HSP90, Nrf2, Nqo1 and HO-1 were significantly decreased. In conclusion, G-Rb1 attenuates oxidative stress in injured spinal cords. The mechanism may at least in part involve the eNOS/Nrf2/HO-1 pathway.

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“…Therefore, basing on the data here discussed and already reported by us 25 , 27 , 28 , 41 and by other research groups 45 , 47 – 49 , we can only suggest the binding location of our molecules on the protein. This region seems to be not completely overlapped both to the allosteric site of Hsp90 (middle:C-terminal domain) 45 , 47 , 48 and to the second nucleotide pocket on Hsp90-C terminus, for which to date, only computational hypothesis can be proposed because its precise physical location in the CTD as well as its exact physiological role are still unclear 49 .…”

Section: Resultsmentioning

confidence: 57%

“… 37 . In order to assess the binding of tested compounds on Hsp90α, we have performed molecular docking experiments using the induced fit docking protocol (Schrödinger Suite) 38 – 40 , to account for flexibility of ligands and receptor 41 . In light of the surface plasmon resonance results and the biological data (see Table S3 , Supplementary Material), we have disclosed two novel not nature-inspired Hsp90 C-terminal inhibitors ( 7 and 10 ).…”

Section: Resultsmentioning

confidence: 99%

Discovery of new molecular entities able to strongly interfere with Hsp90 C-terminal domain

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Chini

et al. 2018

Sci Rep

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Heat shock protein 90 (Hsp90) is an ATP dependent molecular chaperone deeply involved in the complex network of cellular signaling governing some key functions, such as cell proliferation and survival, invasion and angiogenesis. Over the past years the N-terminal protein domain has been fully investigated as attractive strategy against cancer, but despite the many efforts lavished in the field, none of the N-terminal binders (termed “classical inhibitors”), currently in clinical trials, have yet successfully reached the market, because of the detrimental heat shock response (HSR) that showed to induce; thus, recently, the selective inhibition of Hsp90 C-terminal domain has powerfully emerged as a more promising alternative strategy for anti-cancer therapy, not eliciting this cell rescue cascade. However, the structural complexity of the target protein and, mostly, the lack of a co-crystal structure of C-terminal domain-ligand, essential to drive the identification of new hits, represent the largest hurdles in the development of new selective C-terminal inhibitors. Continuing our investigations on the identification of new anticancer drug candidates, by using an orthogonal screening approach, here we describe two new potent C-terminal inhibitors able to induce cancer cell death and a considerable down-regulation of Hsp90 client oncoproteins, without triggering the undesired heat shock response.

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Identification of Limonol Derivatives as Heat Shock Protein 90 (Hsp90) Inhibitors through a Multidisciplinary Approach

Cited by 34 publications

References 65 publications

Virtual Fragment Screening Identification of a Quinoline‐5,8‐dicarboxylic Acid Derivative as a Selective JMJD3 Inhibitor

Virtual Fragment Screening Identification of a Quinoline‐5,8‐dicarboxylic Acid Derivative as a Selective JMJD3 Inhibitor

Effects of ginsenoside Rb1 on oxidative stress injury in rat spinal cords by regulating the eNOS/Nrf2/HO‑1 signaling pathway

Discovery of new molecular entities able to strongly interfere with Hsp90 C-terminal domain

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