Design and biological evaluation of imidazo[1,2-a]pyridines as novel and potent ASK1 inhibitors

Terao, Yoshito; Suzuki, Hideo; Yoshikawa, Masato; Yashiro, Hiroaki; Takekawa, Shiro; Fujitani, Yasushi; Okada, Kengo; Inoue, Yoshihisa; Yamamoto, Yoshio; Nakagawa, Hideyuki; Yao, Shuhei; Kawamoto, Takahiro; Uchikawa, Osamu

doi:10.1016/j.bmcl.2012.10.084

Cited by 57 publications

(33 citation statements)

References 15 publications

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“…It has been demonstrated that inhibition of ASK1 results in decreased phosphorylation of JNK and p38 MAPK [27]. We therefore used the molecular modeling software, AutoDock Vina, to investigate whether or not our inhibitors would overlap with the bound staurosporine when docked to the ATP binding site of ASK1.…”

Section: Resultsmentioning

confidence: 99%

“…This is in agreement with the crystallographically-determined binding of staurosporine, a known ASK1 inhibitor, which was shown by Bunkoczi et al [26] to also pack with its five-ring system against these hydrophobic residues of the binding pocket. Inhibition of ASK1 has been shown to inhibit the activation of JNK and p38 MAPK in pancreatic β cells and could therefore provide a plausible explanation for the effects of AOPHA-Me and PBA on MAPK signaling [27]. …”

Section: Discussionmentioning

confidence: 99%

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Inhibition of JNK and p38 MAPK phosphorylation by 5-(acetylamino)-4-oxo-6-phenyl-2-hexenoic acid methyl ester and 4-phenyl-butenoic acid decreases substance P-induced TNF-α upregulation in macrophages

Lucrezi¹,

Burns²,

Matesic³

et al. 2014

International Immunopharmacology

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The interactions between the immune and nervous systems play an important role in immune and inflammatory conditions. Substance P (SP), the unidecapeptide RPKPQQFFGLM-NH2, is known to upregulate the production of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α. We report here that 5-(acetylamino)-4-oxo-6-phenyl-2-hexenoic acid methyl ester (AOPHA-Me) and 4-phenyl-3-butenoic acid (PBA), two anti-inflammatory compounds developed in our laboratory, reduce SP-stimulated TNF-α expression in RAW 264.7 macrophages. We also show that AOPHA-Me and PBA both inhibit SP-stimulated phosphorylation of JNK and p38 MAPK. Furthermore, molecular modeling studies indicate that both AOPHA-Me and PBA dock at the ATP binding site of apoptosis signal-regulating kinase 1 (ASK1), a member of the MAPKs upstream of both JNK and p38 MAPK, with predicted interaction energies of −7.0 kcal/mol and −5.9 kcal/mol, respectively; this binding overlaps with that of staurosporine, a known inhibitor of ASK1. Taken together, these findings suggest that AOPHA-Me and PBA inhibition of TNF-α expression in SP-stimulated RAW 264.7 macrophages is a consequence of the inhibition JNK and p38 MAPK phosphorylation. We have previously shown that AOPHA-Me and PBA inhibit the amidative bioactivation of SP, which also would be expected to decrease formation of pro-inflammatory cytokines. It is conceivable that this dual action of inhibiting amidation and MAPK phosphorylation may be of some advantage in enhancing the anti-inflammatory activity of a therapeutic molecule.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibition of JNK and p38 MAPK phosphorylation by 5-(acetylamino)-4-oxo-6-phenyl-2-hexenoic acid methyl ester and 4-phenyl-butenoic acid decreases substance P-induced TNF-α upregulation in macrophages

Lucrezi¹,

Burns²,

Matesic³

et al. 2014

International Immunopharmacology

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“…Methyl 2-(4-((6-iodoimidazo[1,2-a]pyridin-2-yl)carbamoyl)phenyl)-2-methylpropanoate (1) was prepared by similar method described in Terao et al 38 A mixture of methyl 2-(4-((6-iodoimidazo[1,2-a]pyridin-2-yl)carbamoyl)phenyl)-2-methylpropanoate (1) (2.1 g, 4.53 mmol) and 2 N NaOH (11.33 ml, 22.67 mmol) in MeOH (25 ml)-THF (12 ml) was stirred at 50 °C for 3 h. After cooling, the mixture was acidified with 2N HCl and diluted with water (50 ml). The precipitate was collected by filtration, washed with water, and dried in vacuo to give 2-(4-((6-iodoimidazo[1,2-a]pyridin- 2-yl)carbamoyl)phenyl)-2-methylpropanoic acid (2) (1.440 g, 3.21 mmol, 70.7%) as a off-white solid.…”

Section: Methodsmentioning

confidence: 99%

CLK-dependent exon recognition and conjoined gene formation revealed with a novel small molecule inhibitor

et al. 2017

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CDC-like kinase phosphorylation of serine/arginine-rich proteins is central to RNA splicing reactions. Yet, the genomic network of CDC-like kinase-dependent RNA processing events remains poorly defined. Here, we explore the connectivity of genomic CDC-like kinase splicing functions by applying graduated, short-exposure, pharmacological CDC-like kinase inhibition using a novel small molecule (T3) with very high potency, selectivity, and cell-based stability. Using RNA-Seq, we define CDC-like kinase-responsive alternative splicing events, the large majority of which monotonically increase or decrease with increasing CDC-like kinase inhibition. We show that distinct RNA-binding motifs are associated with T3 response in skipped exons. Unexpectedly, we observe dose-dependent conjoined gene transcription, which is associated with motif enrichment in the last and second exons of upstream and downstream partners, respectively. siRNA knockdown of CLK2-associated genes significantly increases conjoined gene formation. Collectively, our results reveal an unexpected role for CDC-like kinase in conjoined gene formation, via regulation of 3′-end processing and associated splicing factors.

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“…Imidazopyridine derivatives are a class of novel compounds which have aromatic aldehydes and a pyridine group, and possess medicinal importance [5-7]. Recent studies show imidazopyridine derivatives exhibit potent antitumor activity against breast and pancreatic cancers [8,9].…”

Section: Introductionmentioning

confidence: 99%

Antiproliferative activity of novel imidazopyridine derivatives on castration-resistant human prostate cancer cells

et al. 2014

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Metastatic prostate cancer (mPCa) relapses after a short period of androgen deprivation therapy and becomes the castration-resistant prostate cancer (CR PCa); to which the treatment is limited. Hence, it is imperative to identify novel therapeutic agents towards this patient population. In the present study, antiproliferative activities of novel imidazopyridines were compared. Among three derivatives, PHE, AMD and AMN, examined, AMD showed the highest inhibitory activity on LNCaP C-81 cell proliferation, following dose- and time-dependent manner. Additionally, AMD exhibited significant antiproliferative effect against a panel of PCa cells, but not normal prostate epithelial cells. Further, when compared to AMD, its derivative DME showed higher inhibitory activities on PCa cell proliferation, clonogenic potential and in vitro tumorigenicity. The inhibitory activity was apparently in part due to the induction of apoptosis. Mechanistic studies indicate that AMD and DME treatments inhibited both AR and PI3K/Akt signaling. The results suggest that better understanding of inhibitory mechanisms of AMD and DME could help design novel therapeutic agents for improving the treatment of CR PCa.

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Design and biological evaluation of imidazo[1,2-a]pyridines as novel and potent ASK1 inhibitors

Cited by 57 publications

References 15 publications

Inhibition of JNK and p38 MAPK phosphorylation by 5-(acetylamino)-4-oxo-6-phenyl-2-hexenoic acid methyl ester and 4-phenyl-butenoic acid decreases substance P-induced TNF-α upregulation in macrophages

Inhibition of JNK and p38 MAPK phosphorylation by 5-(acetylamino)-4-oxo-6-phenyl-2-hexenoic acid methyl ester and 4-phenyl-butenoic acid decreases substance P-induced TNF-α upregulation in macrophages

CLK-dependent exon recognition and conjoined gene formation revealed with a novel small molecule inhibitor

Antiproliferative activity of novel imidazopyridine derivatives on castration-resistant human prostate cancer cells

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