Preclinical Evaluation of AZ12601011 and AZ12799734, Inhibitors of Transforming Growth Factor β Superfamily Type 1 Receptors.

Lindsay C. Spender, G. John Ferguson, Gareth D. Hughes, Barry R. Davies, Frederick W. Goldberg, Blanca Herrera, Richard G. Taylor, Lauren Strathearn, Owen J. Sansom, Simon T. Barry, Gareth Inman (Lead / Corresponding author)

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    The transforming growth factor β (TGF β) superfamily includes TGF β, 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 TGF β 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 β receptor 1 (TGFBR1) kinase inhibitors designed to target TGF β 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 = 18 and 47 nM, respectively) were more effective inhibitors of TGF β-induced reporter activity than SB-431542 [4-[4-(1,3-benzodioxol-5-yl)-5-(2-pyridinyl)-1H-imidazol-2-yl]benzamide] (IC 50 = 84 nM) and LY2157299 [4-[2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]quinoline-6-carboxamide monohydrate]] (galunisertib) (IC 50 = 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 TGF β-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 TGF β- and BMP-regulated signaling pathways to disease states.

    Original languageEnglish
    Pages (from-to)222-234
    Number of pages13
    JournalMolecular Pharmacology
    Issue number2
    Early online date14 Jan 2019
    Publication statusPublished - 1 Feb 2019


    • Activin Receptors, Type I/metabolism
    • Animals
    • Bone Morphogenetic Proteins/metabolism
    • Cell Line
    • Cell Proliferation/drug effects
    • DNA-Binding Proteins
    • Mice
    • NIH 3T3 Cells
    • Neoplasm Metastasis/pathology
    • Phosphorylation/drug effects
    • Protein Kinase Inhibitors/pharmacology
    • Receptor, Transforming Growth Factor-beta Type I/metabolism
    • Signal Transduction/drug effects
    • Smad2 Protein/metabolism

    ASJC Scopus subject areas

    • Molecular Medicine
    • Pharmacology


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