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

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Abstract
The transforming growth factor beta (TGFβ superfamily includes TGFβ, activins, inhibins and bone morphogenetic proteins (BMPs). These extracellular ligands have essential roles in normal tissue homeostasis by co-ordinately regulating cell proliferation, differentiation, and migration. Aberrant signalling of superfamily members, however, is associated with fibrosis as well as tumourigenesis, cancer progression, metastasis and drug-resistance mechanisms in a variety of cancer sub-types. Given their involvement in human disease, the identification of novel selective inhibitors of TGFβsuperfamily 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 characterise the biological effects of two TGFBR1 kinase inhibitors designed to target TGFβ signalling. AZ12601011 (structure previously undisclosed) and AZ12799734 (IC50s, 18nM and 47nM respectively) were more effective inhibitors of TGFβ-induced reporter activity than SB-431542 (IC50, 84nM) and LY2157299 (galunisertib) (IC50, 380nM). AZ12601011 inhibited phosphorylation of SMAD2 via the type 1 receptors ALK4, TGFBR1 and ALK7. AZ12799734, however, is a pan TGFβ/BMP inhibitor, inhibiting receptor-mediated phosphorylation of SMAD1 by ALK1, BMPR1A and BMPR1B 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 tumour growth and metastasis to the lungs in a 4T1 syngeneic orthotopic mammary tumour model. These inhibitors provide new reagents for investigating in vitro and in vivo pathogenic processes and the contribution of TGFβ and BMP regulated signalling pathways to disease states.

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