Synthesis and biological evaluation of 1-substituted-3-(6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors

Jin, Cheng; Krishnaiah, Maddeboina; Sreenu, D.; Subrahmanyam, Vura Bala; Rao, Kota Sudhakar; Mohan, Annaji Venkata Nagendra; Park, Chul‐Yong; Son, Jee‐Yeon; Sheen, Yhun Yhong; Kim, Dae‐Kee

doi:10.1016/j.bmcl.2011.08.064

Cited by 33 publications

(10 citation statements)

References 35 publications

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“…They speculated JNK‐dependent, Smad2/3‐independent pathway from the similar attenuating effect of ALK5 inhibitor, SB431542 and JNK inhibitor, SP600125 on Eomes repression in T cells stimulated with TCR and TGF‐β. However, specificity of ALK5 inhibitors for Smad‐mediated TGF‐β signalling pathway (Akhurst & Hata, ; Flavell et al, ; Hawinkels & ten Dijke, ; Jin et al, ) and cooperation of Smad3 and Smad4 with c‐Jun/c‐Fos to mediate TGF‐β‐induced transcription (Zhang et al, ) suggest that both Smad3/4 and JNK pathways are involved in TGF‐β‐induced Eomes suppression.…”

Section: Discussionmentioning

confidence: 99%

“…TGF‐β type I receptor (TβRI) phosphorylates TGF‐β receptor‐activated Smads (R‐Smads), Smad2 and Smad3, which form heteromeric complexes with the common Smad, Smad4, to translocate into the nuclei, where they regulate the target gene transcription (Massague et al, ). Activin receptor‐like kinase5 (ALK5) inhibitors are the small molecule inhibitors, which block phosphorylation of R‐Smads by occupying the ATP binding site of TβRI domain (Jin et al, ). On the basis of a selective, imidazole‐based ALK5 inhibitor, 4‐(4‐(benzo[ d ][1,3]dioxol‐5‐yl)‐5‐(pyridin‐2‐yl)‐1 H ‐imidazol‐2‐yl)benzamide, SB‐431542 (Callahan et al, ) as a lead compound, we designed and synthesized an orally bioavailable ALK5 inhibitor, N ‐((4‐([1,2,4]triazolo[1,5‐ a ]pyridin‐6‐yl)‐5‐(6‐methylpyridin‐2‐yl)‐1 H ‐imidazol‐2‐yl)methyl)‐2‐fluoroaniline, EW‐7197 (Kim et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Activin receptor‐like kinase5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby derepressing eomesodermin in cytotoxic T lymphocytes

et al. 2013

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Varieties of transforming growth factor-β (TGF-β) antagonists have been developed to intervene with excessive TGF-β signalling activity in cancer. Activin receptor-like kinase5 (ALK5) inhibitors antagonize TGF-β signalling by blocking TGF-β receptor-activated Smad (R-Smad) phosphorylation. Here we report the novel mechanisms how ALK5 inhibitors exert a therapeutic effect on a mouse B16 melanoma model. Oral treatment with a novel ALK5 inhibitor, EW-7197 (2.5 mg/kg daily) or a representative ALK5 inhibitor, LY-2157299 (75 mg/kg bid) suppressed the progression of melanoma with enhanced cytotoxic T-lymphocyte (CTL) responses. Notably, ALK5 inhibitors not only blocked R-Smad phosphorylation, but also induced ubiquitin-mediated degradation of the common Smad, Smad4 mainly in CD8+ T cells in melanoma-bearing mice. Accordingly, T-cell-specific deletion of Smad4 was sufficient to suppress the progression of melanoma. We further identified eomesodermin (Eomes), the T-box transcription factor regulating CTL functions, as a specific target repressed by TGF-β via Smad4 and Smad3 in CD8+ T cells. Thus, ALK5 inhibition enhances anti-melanoma CTL responses through ubiquitin-mediated degradation of Smad4 in addition to the direct inhibitory effect on R-Smad phosphorylation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Activin receptor‐like kinase5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby derepressing eomesodermin in cytotoxic T lymphocytes

et al. 2013

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“…Several [ 1 , 2 , 4 ]triazolo[1,5- a ]pyridine-bearing pyrazole moieties were prepared by Jin et al and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. The compound 231 exerted the maximun anticancer actvity with IC 50 of 0.57 nM [ 136 ]. Newhouse et al reported the synthesis and anticancer activity of pyrazole derivatives.…”

Section: Pharmacological Activitiesmentioning

confidence: 99%

Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review

et al. 2018

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Pyrazole and its derivatives are considered a pharmacologically important active scaffold that possesses almost all types of pharmacological activities. The presence of this nucleus in pharmacological agents of diverse therapeutic categories such as celecoxib, a potent anti-inflammatory, the antipsychotic CDPPB, the anti-obesity drug rimonabant, difenamizole, an analgesic, betazole, a H2-receptor agonist and the antidepressant agent fezolamide have proved the pharmacological potential of the pyrazole moiety. Owing to this diversity in the biological field, this nucleus has attracted the attention of many researchers to study its skeleton chemically and biologically. This review highlights the different synthesis methods and the pharmacological properties of pyrazole derivatives. Studies on the synthesis and biological activity of pyrazole derivatives developed by many scientists around the globe are reported.

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“…Carbothioamide-substituted pyrazole and isoxazolidine are important building blocks of many pharmacologically active compounds [73,74,75,76]. Both fragments display enhanced biological activity upon introduction to another compound [77,78,79]. Two series of carbothioamide-substituted isoxazolidine isosteviol analogues containing pyrazole and isoxazolidine ring fused with the isosteviol structure on integration exhibited novel antitumor activity [73].…”

Section: Pharmacological Activities Of Isosteviol Derivativesmentioning

confidence: 99%

Bioactivity Profile of the Diterpene Isosteviol and its Derivatives

et al. 2019

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Steviosides, rebaudiosides and their analogues constitute a major class of naturally occurring biologically active diterpene compounds. The wide spectrum of pharmacological activity of this group of compounds has developed an interest among medicinal chemists to synthesize, purify, and analyze more selective and potent isosteviol derivatives. It has potential biological applications and improves the field of medicinal chemistry by designing novel drugs with the ability to cope against resistance developing diseases. The outstanding advancement in the design and synthesis of isosteviol and its derivative has proved its effectiveness and importance in the field of medicinal chemical research. The present review is an effort to integrate recently developed novel drugs syntheses from isosteviol and potentially active pharmacological importance of the isosteviol derivatives covering the recent advances.

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Synthesis and biological evaluation of 1-substituted-3-(6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors

Cited by 33 publications

References 35 publications

Activin receptor‐like kinase5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby derepressing eomesodermin in cytotoxic T lymphocytes

Activin receptor‐like kinase5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby derepressing eomesodermin in cytotoxic T lymphocytes

Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review

Bioactivity Profile of the Diterpene Isosteviol and its Derivatives

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