Small-Molecule Inhibitors of Cytokine-Mediated STAT1 Signal Transduction in β-Cells with Improved Aqueous Solubility

Scully, Stephen S.; Tang, Alicia J.; Lundh, Morten; Mosher, Carrie M.; Perkins, Kedar M.; Wagner, Bridget K.

doi:10.1021/jm400397x

Cited by 22 publications

(21 citation statements)

References 22 publications

(49 reference statements)

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“…The values of aqueous solubility of 28 and 29 in 1/15 M phosphate buffer (pH 7.4) were quite low (,0.001 mg/mL). Surprisingly, an increase of dihedral angle (33) resulted in greater solubility in the phosphate buffer than did a decrease of hydrophobicity (34) in this case. All the compounds shown in Table 31.6 had higher solubility than the parent compounds.…”

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confidence: 67%

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Improving the Water-Solubility of Compounds by Molecular Modification to Disrupt Crystal Packing

Ishikawa

Hashimoto

2015

The Practice of Medicinal Chemistry

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confidence: 67%

“…Increase of the dihedral angle was also useful for improvement in solubility of benzamides, anilides, and phenylureas. [33]. The melting point of 40 was lower than that of 39 (Table 31.7).…”

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confidence: 88%

Improving the Water-Solubility of Compounds by Molecular Modification to Disrupt Crystal Packing

Ishikawa

Hashimoto

2015

The Practice of Medicinal Chemistry

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“…Like BRD0476, WP1130 decreased cytokine-induced phosphorylation of STAT1 in INS-1E cells after 30 min treatment (Figure 4c). Importantly, neither BRD6283, an inactive analog of BRD0476, 26 nor VM001, an inactive analog of WP1130, 32 had any effect on STAT1 phosphorylation (Figure 4c). WP1130 induced significant cellular toxicity at the same concentrations at which it inhibited STAT1 phosphorylation (data not shown), probably due to targeting other deubiquitinases, precluding us from determining its suppressive effects on β -cell apoptosis.…”

Section: Resultsmentioning

confidence: 98%

Kinase-Independent Small-Molecule Inhibition of JAK-STAT Signaling

Chou

Vetere²,

Choudhary

et al. 2015

J. Am. Chem. Soc.

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Phenotypic cell-based screening is a powerful approach to small-molecule discovery, but a major challenge of this strategy lies in determining the intracellular target and mechanism of action (MoA) for validated hits. Here, we show that the small-molecule BRD0476, a novel suppressor of pancreatic β-cell apoptosis, inhibits interferon-gamma (IFN-γ)-induced Janus kinase 2 (JAK2) and signal transducer and activation of transcription 1 (STAT1) signaling to promote β-cell survival. However, unlike common JAK-STAT pathway inhibitors, BRD0476 inhibits JAK-STAT signaling without suppressing the kinase activity of any JAK. Rather, we identified the deubiquitinase ubiquitin-specific peptidase 9X (USP9X) as an intracellular target, using a quantitative proteomic analysis in rat β cells. RNAi-mediated and CRISPR/Cas9 knockdown mimicked the effects of BRD0476, and reverse chemical genetics using a known inhibitor of USP9X blocked JAK-STAT signaling without suppressing JAK activity. Site-directed mutagenesis of a putative ubiquitination site on JAK2 mitigated BRD0476 activity, suggesting a competition between phosphorylation and ubiquitination to explain small-molecule MoA. These results demonstrate that phenotypic screening, followed by comprehensive MoA efforts, can provide novel mechanistic insights into ostensibly well-understood cell signaling pathways. Furthermore, these results uncover USP9X as a potential target for regulating JAK2 activity in cellular inflammation.

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“…Because of the critical role of β cell dysfunction and death on the onset and progression of diabetes, HTS efforts have been made to identify small molecules that protect β cells. 22, 31–33 These HTSs are primarily based on β cell survival-based phenotypic screens, in which β cells are subjected to stress (e.g., cytokines or ER stress)-mediated death and small molecules that suppress the stress-mediated death are identified. This approach has discovered several interesting β cell-protective chemotypes, although significant efforts are needed to identify the protein or pathway targets of these molecules.…”

Section: Resultsmentioning

confidence: 99%

Identification of 1,2,3-triazole derivatives that protect pancreatic β cells against endoplasmic reticulum stress-mediated dysfunction and death through the inhibition of C/EBP-homologous protein expression

Duan

Arora

et al. 2016

Bioorganic & Medicinal Chemistry

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The C/EBP-homologous protein (CHOP) acts as a mediator of endoplasmic reticulum (ER) stress-induced pancreatic insulin-producing β cell death, a key element in the pathogenesis of diabetes. Chemicals that inhibit the expression of CHOP might therefore protect β cells from ER stress-induced apoptosis and prevent or ameliorate diabetes. Here, we used high-throughput screening to identify a series of 1,2,3-triazole amide derivatives that inhibit ER stress-induced CHOP-luciferase reporter activity. Our SAR studies indicate that compounds with an N,1-diphenyl-5-methyl-1H-1,2,3-triazole-4-carboxamide backbone potently protect β cell against ER stress. Several representative compounds inhibit ER stress-induced up-regulation of CHOP mRNA and protein, without affecting the basal level of CHOP expression. We further show that a 1,2,3-triazole derivative 4e protects β cell function and survival against ER stress in a CHOP-dependent fashion, as it is inactive in CHOP-deficient β cells. Finally, we show that 4e significantly lowers blood glucose levels and increases concomitant β cell survival and number in a streptozotocin-induced diabetic mouse model. Identification of small molecule inhibitors of CHOP expression that prevent ER stress-induced β cell dysfunction and death may provide a new modality for the treatment of diabetes.

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Small-Molecule Inhibitors of Cytokine-Mediated STAT1 Signal Transduction in β-Cells with Improved Aqueous Solubility

Cited by 22 publications

References 22 publications

Improving the Water-Solubility of Compounds by Molecular Modification to Disrupt Crystal Packing

Improving the Water-Solubility of Compounds by Molecular Modification to Disrupt Crystal Packing

Kinase-Independent Small-Molecule Inhibition of JAK-STAT Signaling

Identification of 1,2,3-triazole derivatives that protect pancreatic β cells against endoplasmic reticulum stress-mediated dysfunction and death through the inhibition of C/EBP-homologous protein expression

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