Format

Send to

Choose Destination
Mol Pharmacol. 2019 Feb;95(2):222-234. doi: 10.1124/mol.118.112946. Epub 2018 Nov 20.

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

Author information

1
Cancer Research UK Beatson Institute, Garscube Estate, Bearsden, Glasgow, United Kingdom (L.C.S., G.J.F., B.H., O.J.S., G.J.I.);Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom (O.J.S., G.J.I.) Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee, United Kingdom (R.G.T., L.S.S.); and AstraZeneca Bioscience, Oncology (G.D.H., S.T.B., B.R.D.) and Medicinal Chemistry, Oncology (F.W.G.), IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom.
2
Cancer Research UK Beatson Institute, Garscube Estate, Bearsden, Glasgow, United Kingdom (L.C.S., G.J.F., B.H., O.J.S., G.J.I.);Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom (O.J.S., G.J.I.) Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee, United Kingdom (R.G.T., L.S.S.); and AstraZeneca Bioscience, Oncology (G.D.H., S.T.B., B.R.D.) and Medicinal Chemistry, Oncology (F.W.G.), IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom g.inman@beatson.gla.ac.uk.

Abstract

The transforming growth factor β (TGFβ) superfamily includes TGFβ, 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 TGFβ 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 TGFβ 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] (IC50 = 18 and 47 nM, respectively) were more effective inhibitors of TGFβ-induced reporter activity than SB-431542 [4-[4-(1,3-benzodioxol-5-yl)-5-(2-pyridinyl)-1H-imidazol-2-yl]benzamide] (IC50 = 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) (IC50 = 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 TGFβ-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 TGFβ- and BMP-regulated signaling pathways to disease states.

PMID:
30459156
DOI:
10.1124/mol.118.112946

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center