Abstract
Transforming growth factor-β (TGFβ) is an important driver of tumor growth via intrinsic and extrinsic mechanisms, and is therefore an attractive target for developing cancer therapeutics. Using preclinical models, we characterized the anti-tumor activity of a small molecule inhibitor of TGFβ receptor I (TGFβRI), galunisertib (LY2157299 monohydrate). Galunisertib demonstrated potent and selective inhibition of TGFβRI with corresponding inhibition of downstream signaling via inhibition of SMAD phosphorylation (pSMAD). Galunisertib also inhibited TGFβ-induced pSMAD in vivo, which enabled a pharmacokinetic/pharmacodynamic profile in Calu6 and EMT6-LM2 tumors. Galunisertib demonstrated anti-tumor activity including inhibition of tumor cell migration and mesenchymal phenotype, reversal of TGFβ-mediated immune-suppression, and tumor growth delay. A concentration-effect relationship was established with a dosing schedule to achieve the optimal level of target modulation. Finally, a rat model demonstrated a correlation between galunisertib-dependent inhibition of pSMAD in tumor tissues and in PBMCs, supporting the use of PBMCs for assessing pharmacodynamic effects.Galunisertib has been tested in several clinical studies with evidence of anti-tumor activity observed in subsets of patients. Here, we demonstrate that galunisertib inhibits a number of TGFβ-dependent functions leading to anti-tumor activity. The enhanced understanding of galunisertib provides rationale for further informed clinical development of TGFβ pathway inhibitors.
Highlights
The transforming growth factor beta (TGFβ) superfamily is an important group of signaling receptors triggered by a broad set of ligands that are critical for development and tissue homeostasis
Galunisertib is a TGFβ receptor I (TGFβRI) kinase inhibitor of the dihydropyrrolopyrazole class that was synthesized in a four-step convergent approach to generate a chemical compound with the formula 4-[2-(6-methylpyridin-2-yl)5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]quinoline6-carboxamide monohydrate (Figure 1A) [26]
These analyses showed that galunisertib is a highly selective TGFβRI inhibitor with an IC50 for the TGFβRI/Alk5 kinase domain of 0.172 μM (Figure 1C, Table 1)
Summary
The transforming growth factor beta (TGFβ) superfamily is an important group of signaling receptors triggered by a broad set of ligands that are critical for development and tissue homeostasis. The TGFβ ligand superfamily includes three TGFβ isoforms (TGFβ1, TGFβ2 and TGFβ3), activins, growth and differentiation factors, BMPs, inhibins, nodal, and anti-mullerian hormone [1,2]. The TGFβ isoforms represent prototypic members of the TGFβ superfamily and signal via a TGFβ receptor I (TGFβRI) and TGFβ receptor II (TGFβRII) heterodimeric complex; in addition to their function in normal growth and development, they play key roles www.impactjournals.com/oncotarget in several disease states including cancer [2,3,4]. Blockade of the TGFβ pathway is an attractive anti-cancer therapeutic approach
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