Rapid Generation of a High Quality Lead for Transforming Growth Factor-β (TGF-β) Type I Receptor (ALK5)

Goldberg, Frederick W.; Ward, Richard A.; Powell, Stephen Joseph; Debreczeni, J.; Norman, Richard A.; Roberts, Nicola; Dishington, Allan; Gingell, H.; Wickson, Kate; Roberts, Andrew

doi:10.1021/jm900807w

Cited by 32 publications

(19 citation statements)

References 26 publications

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“…6 Continuous flow technologies allow coupling reactions to be safely performed at high temperatures and/or pressures and avoid the handling of reactive or dangerous intermediates. 6 Continuous flow technologies allow coupling reactions to be safely performed at high temperatures and/or pressures and avoid the handling of reactive or dangerous intermediates.…”

mentioning

confidence: 99%

Oscillatory three-phase flow reactor for studies of bi-phasic catalytic reactions

2015

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A multi-phase flow strategy, based on oscillatory motion of a bi-phasic slug within a fluorinated ethylene propylene (FEP) tubular reactor, under inert atmosphere, is designed and developed to address mixing and mass transfer limitations associated with continuous slug flow chemistry platforms for studies of bi-phasic catalytic reactions. The technique is exemplified with C-C and C-N Pd catalyzed coupling reactions.

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confidence: 99%

Oscillatory three-phase flow reactor for studies of bi-phasic catalytic reactions

2015

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“…The plates were developed with QuantaBlu (Thermo Fisher Scientific, Loughborough, UK) using the manufacturer's recommended protocol and read on a Tecan Spectro-Fluor (Tecan, Switzerland) using excitation at 340/465-nm emission. (Goldberg et al, 2009). (B) TGFb-inducible SMAD3/4-dependent CAGA12 promoter-luciferase reporter bioassay carried out in both the absence (2) and presence (+) of exogenous addition of TGFb1 (1 ng/mL) for 8 hours.…”

Section: Synthetic Procedures For Az12601011mentioning

confidence: 99%

“…AZ12601011 2-(2-pyridinyl)-4-(1H-pyrrolo[3,2-c]pyridin-1yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine; structure previously undisclosed] and AZ12799734 [4-({4-[(2,6-dimethyl-3-pyridinyl)oxy]-2-pyridinyl}amino)benzenesulfonamide] (Goldberg et al, 2009;Anderton et al, 2011) are two selective TGFBR1 inhibitors. AZ12601011 and AZ12799734 inhibit TGFBR1 kinase activity (competition binding) with K d values of 2.9 and 740 nM, respectively.…”

Section: Introductionmentioning

confidence: 99%

Preclinical Evaluation of AZ12601011 and AZ12799734, Inhibitors of Transforming Growth FactorβSuperfamily Type 1 Receptors

et al. 2018

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The transforming growth factor b (TGFb) superfamily includes TGFb, activins, inhibins, and bone morphogenetic proteins (BMPs). These extracellular ligands have essential roles in normal tissue homeostasis by coordinately regulating cell proliferation, differentiation, and migration. Aberrant signaling of superfamily members, however, is associated with fibrosis as well as tumorigenesis, cancer progression, metastasis, and drug-resistance mechanisms in a variety of cancer subtypes. Given their involvement in human disease, the identification of novel selective inhibitors of TGFb superfamily receptors is an attractive therapeutic approach. Seven mammalian type 1 receptors have been identified that have context-specific roles depending on the ligand and the complex formation with the type 2 receptor. Here, we characterize the biologic effects of two transforming growth factor b receptor 1 (TGFBR1) kinase inhibitors designed to target TGFb signaling. AZ12601011 [2-(2-pyridinyl)-4-(1H-pyrrolo[3,2-c]pyridin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine]; structure previously undisclosed] and AZ12799734 [4-({4-[(2,6-dimethyl-3-pyridinyl) oxy]-2-pyridinyl}amino)benzenesulfonamide] (IC 50 5 18 and 47 nM, respectively) were more effective inhibitors of TGFb-induced reporter activity than SB-431542 [4-[4-(1,3-benzodioxol-5-yl)-5-(2-pyridinyl)-1H-imidazol-2-yl]benzamide] (IC 50 5 84 nM) and LY2157299 [4-[2-(6-methylpyridin-2-yl)-5,6-dihydro-4Hpyrrolo[1,2-b]pyrazol-3-yl]quinoline-6-carboxamide monohydrate]] (galunisertib) (IC 50 5 380 nM). AZ12601011 inhibited phosphorylation of SMAD2 via the type 1 receptors activin A receptor type 1B (ALK4), TGFBR1, and activin A receptor type 1C (ALK7). AZ12799734, however, is a pan TGF/BMP inhibitor, inhibiting receptor-mediated phosphorylation of SMAD1 by activin A receptor type 1L, bone morphogenetic protein receptor type 1A, and bone morphogenetic protein receptor type 1B and phosphorylation of SMAD2 by ALK4, TGFBR1, and ALK7. AZ12601011 was highly effective at inhibiting basal and TGFb-induced migration of HaCaT keratinocytes and, furthermore, inhibited tumor growth and metastasis to the lungs in a 4T1 syngeneic orthotopic mammary tumor model. These inhibitors provide new reagents for investigating in vitro and in vivo pathogenic processes and the contribution of TGFb-and BMP-regulated signaling pathways to disease states.

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“…3,[11][12][13][14][15][16][17][18][19][20] In a previous paper, we described the discovery of 1 21) (ALK5 IC 50 =2.7 nm, Smad2/3 IC 50 =8.7 nm), which was the most potent inhibitor of ALK5. Moreover, we reported that 1 inhibited Smad2 phosphorylation in mouse skin in such a way as to block the TGF-β/Smad signals after the topical application.…”

Section: Discovery Of 7-methoxy-6-[4-(4-methyl-13-thiazol-2-yl)-1h-imentioning

confidence: 99%

Discovery of 7-Methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1<i>H</i>-imidazol-5-yl]-1,3-benzothiazole (TASP0382088): A Potent and Selective Transforming Growth Factor-β Type I Receptor Inhibitor as a Topical Drug for Alopecia

et al. 2013

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7-Methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole 11 (TASP0382088) was synthesized and evaluated as transforming growth factor-β (TGF-β) type I receptor (also known as activin receptor-like kinase 5 or ALK5) inhibitor. Compound 11, a potent and selective ALK5 inhibitor, exhibited good enzyme inhibitory activity (IC 50 =4.8 nm) as well as inhibitory activity against TGF-β-induced Smad2/3 phosphorylation at a cellular level (IC 50 =17 nm). The introduction of a methoxy group to the benzothiazole ring in 1 and the break up of the planarity between the imidazole ring and the thiazole ring improved the solubility in the lotion base of 11. Furthermore, the topical application of 3% 11 lotion significantly inhibited Smad2 phosphorylation in mouse skin at 8 h after application (71% inhibition, compared with vehicle-treated animals).

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Rapid Generation of a High Quality Lead for Transforming Growth Factor-β (TGF-β) Type I Receptor (ALK5)

Cited by 32 publications

References 26 publications

Oscillatory three-phase flow reactor for studies of bi-phasic catalytic reactions

Oscillatory three-phase flow reactor for studies of bi-phasic catalytic reactions

Preclinical Evaluation of AZ12601011 and AZ12799734, Inhibitors of Transforming Growth FactorβSuperfamily Type 1 Receptors

Discovery of 7-Methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1<i>H</i>-imidazol-5-yl]-1,3-benzothiazole (TASP0382088): A Potent and Selective Transforming Growth Factor-β Type I Receptor Inhibitor as a Topical Drug for Alopecia

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