Synthesis and biological evaluation of 1-substituted-3(5)-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors

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

doi:10.1016/j.ejmech.2011.05.063

Cited by 32 publications

(24 citation statements)

References 40 publications

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“…The inhibitors K02288, ML347, and LDN-193189, are known inhibitors of the SMAD1/5/8-pathway via BMP type 1 receptors (e.g., ALK1, ALK2, ALK3 and ALK6) [28][29][30]. The inhibitors SB431542, RepSox, and ZC-47-C95 are described as inhibitors of the SMAD2/3 pathway via activin/TGF-β type 1 receptors (e.g., ALK4, ALK5 and ALK7) [24,31,32]. A table describing relative specificities of the inhibitors is shown ( Supplementary Table S2).…”

Section: Effect Of Small Molecule Inhibitors On Activin-induced Smad mentioning

confidence: 99%

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Activins as Dual Specificity TGF-β Family Molecules: SMAD-Activation via Activin- and BMP-Type 1 Receptors

et al. 2020

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Activins belong to the transforming growth factor (TGF)-β family of multifunctional cytokines and signal via the activin receptors ALK4 or ALK7 to activate the SMAD2/3 pathway. In some cases, activins also signal via the bone morphogenetic protein (BMP) receptor ALK2, causing activation of the SMAD1/5/8 pathway. In this study, we aimed to dissect how activin A and activin B homodimers, and activin AB and AC heterodimers activate the two main SMAD branches. We compared the activin-induced signaling dynamics of ALK4/7-SMAD2/3 and ALK2-SMAD1/5 in a multiple myeloma cell line. Signaling via the ALK2-SMAD1/5 pathway exhibited greater differences between ligands than signaling via ALK4/ALK7-SMAD2/3. Interestingly, activin B and activin AB very potently activated SMAD1/5, resembling the activation commonly seen with BMPs. As SMAD1/5 was also activated by activins in other cell types, we propose that dual specificity is a general mechanism for activin ligands. In addition, we found that the antagonist follistatin inhibited signaling by all the tested activins, whereas the antagonist cerberus specifically inhibited activin B. Taken together, we propose that activins may be considered dual specificity TGF-β family members, critically affecting how activins may be considered and targeted clinically.

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Section: Effect Of Small Molecule Inhibitors On Activin-induced Smad mentioning

confidence: 99%

“…Biomolecules 2020, 10, x 6 of 15 inhibitors of the SMAD2/3 pathway via activin/TGF-β type 1 receptors (e.g., ALK4, ALK5 and ALK7) [24,31,32]. A table describing relative specificities of the inhibitors is shown (Supplementary Table S2).…”

Section: Effect Of Small Molecule Inhibitors On Activin-induced Smad mentioning

confidence: 99%

Activins as Dual Specificity TGF-β Family Molecules: SMAD-Activation via Activin- and BMP-Type 1 Receptors

et al. 2020

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“…Among them, clinical candidates, compounds 3 and 4 have progressed to Phase II and Phase I trials as antitumor agents, respectively. We previously showed that a series of compounds, denoted as 5, containing the quinoxaline moiety, except for the 2,3-dimethyl substituted analogs, showed significant ALK5 inhibition in an enzymatic assay [14]. This series of compounds was selective for ALK5, compared with p38α MAP kinase.…”

Section: Introductionmentioning

confidence: 94%

“…The 6-(dimethylamino)picolinaldehyde (8) [23] and 4-methylthiazole-2-carbaldehyde (9) were treated with aniline and diphenyl phosphite in i-PrOH at room temperature to give the (phenylamino)methylphosphonates 10a and 10b in 90% and 70% yields, respectively. Coupling of the 10a and 10b with quinoxaline-6-carbaldehyde [24] in a mixture of THF and i-PrOH (4:1) at room temperature in the presence of Cs2CO3, followed by hydrolysis with 1 N HCl, produced the corresponding monoketones 11a and 11b in 71% and 52% yields, respectively [14]. Treatment of 11a and 11b with N,N-dimethylformamide dimethyl acetal (DMF•DMA) in N,N-dimethylformamide (DMF) at 80 o C, followed by cyclization with hydrazine monohydrate in absolute EtOH, produced the pyrazoles 12a and 12b in 68% and 71% yields, respectively [25].…”

Section: Synthesismentioning

confidence: 99%

Synthesis and Biological Evaluation of 3-Substituted-4-(quinoxalin-6-yl) Pyrazoles as Selective ALK5 Inhibitors

Zhao¹,

Guo²,

Xue³

et al. 2018

Preprint

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The transforming growth factor-β (TGF-β), in which overexpression have been associated with various diseases, has become an attractive molecular target for the treatment of cancers. Three series of 3-substituted-4-(quinoxalin-6-yl) pyrazoles 14a–h, 15a–h, 16a–h, 22a, 22b, 22d, 23a, 23b, 23d, 24b, and 24d were synthesized and evaluated for their activin receptor-like kinase 5 (ALK5) and p38α mitogen activated protein (MAP) kinase inhibitory activity in an enzymatic assays. Among these compounds, the most active compound 16f inhibited ALK5 phosphorylation with an IC50 value of 0.28 µM, with 98% inhibition at 10 µM. Compound 16f also had good selectivity index of >35 against p38α MAP kinase, with 9.0-fold more selective than clinical candidate, compound 3 (LY-2157299). Molecular docking study was performed to identify the mechanism of action of the synthesized compounds and their good binding interactions were observed. ADMET prediction of good active compounds showed that these ones possess good pharmacokinetics and drug-likeness behavior.

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“…Other reported quinoxaline scaffolds with improved kinase inhibitory activity were 188 [173], 189 [174], 190 [175], 191 [176], 192 [176] and 193 [177]. <<<<Fig.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Present status of quinoxaline motifs: Excellent pathfinders in therapeutic medicine

Ajani

2014

European Journal of Medicinal Chemistry

104

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Synthesis and biological evaluation of 1-substituted-3(5)-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors

Cited by 32 publications

References 40 publications

Activins as Dual Specificity TGF-β Family Molecules: SMAD-Activation via Activin- and BMP-Type 1 Receptors

Activins as Dual Specificity TGF-β Family Molecules: SMAD-Activation via Activin- and BMP-Type 1 Receptors

Synthesis and Biological Evaluation of 3-Substituted-4-(quinoxalin-6-yl) Pyrazoles as Selective ALK5 Inhibitors

Present status of quinoxaline motifs: Excellent pathfinders in therapeutic medicine

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