Preclinical assessment of galunisertib (LY2157299 monohydrate), a first-in-class transforming growth factor-β receptor type I inhibitor

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.

Novel transforming growth factor beta receptor I kinase inhibitor galunisertib (LY2157299) in advanced hepatocellular carcinoma

“…Galunisertib (LY2157299) is a small molecule that selectively inhibits the serine/threonine kinase of the TGF‐β receptor type I (TGF‐β RI/ALK5) . Galunisertib had an acceptable safety profile in phase 1 studies and may be well tolerated in patients with HCC .…”

Circular RNA cESRP1 sensitises small cell lung cancer cells to chemotherapy by sponging miR-93-5p to inhibit TGF-β signalling

“…Our results suggested that cESRP1 effectively increases the abundance of Smad7/p21 (CDKN1A) and formed a double-negative feedback loop to abolish the effect of the TGF-β/Smad signalling pathway. A growing number of clinical studies have shown that anti-TGF-β therapy has an acceptable safety/tolerability profile and exhibits anti-tumour activity in subsets of patients [70][71][72]. In this study, we used an SCLC chemoresistant cell line orthotopic xenograft model and observed that the TGF-β signalling inhibitor LY2157299 (galunisertib), which was bioavailable, effectively suppressed the TGF-β signalling pathway, augmenting tumour chemotherapy responsiveness in combination with chemotherapeutic drugs.…”

Targeting TGF βR2‐mutant tumors exposes vulnerabilities to stromal TGF β blockade in pancreatic cancer

“…TGFβ is an attractive therapeutic target for enhancing the effects of chemotherapy and immune therapy. Multiple therapeutic strategies targeting the TGFβ pathway are undergoing clinical studies in different cancers including PDA (de Gramont et al , ; Yingling et al , ). Our study underscores the importance of stratifying the patients in these studies such that those with tumor cell mutations in TGFβ signaling would be candidates for inhibition of stromal TGFβ signaling in combination with standard or immune therapy.…”