Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway

Abstract

Transforming growth factor-beta (TGF-β) signaling regulates a wide range of biological processes. TGF-β plays an important role in tumorigenesis and contributes to the hallmarks of cancer, including tumor proliferation, invasion and metastasis, inflammation, angiogenesis, and escape of immune surveillance. There are several pharmacological approaches to block TGF-β signaling, such as monoclonal antibodies, vaccines, antisense oligonucleotides, and small molecule inhibitors. Galunisertib (LY2157299 monohydrate) is an oral small molecule inhibitor of the TGF-β receptor I kinase that specifically downregulates the phosphorylation of SMAD2, abrogating activation of the canonical pathway. Furthermore, galunisertib has antitumor activity in tumor-bearing animal models such as breast, colon, lung cancers, and hepatocellular carcinoma. Continuous long-term exposure to galunisertib caused cardiac toxicities in animals requiring adoption of a pharmacokinetic/pharmacodynamic-based dosing strategy to allow further development. The use of such a pharmacokinetic/pharmacodynamic model defined a therapeutic window with an appropriate safety profile that enabled the clinical investigation of galunisertib. These efforts resulted in an intermittent dosing regimen (14 days on/14 days off, on a 28-day cycle) of galunisertib for all ongoing trials. Galunisertib is being investigated either as monotherapy or in combination with standard antitumor regimens (including nivolumab) in patients with cancer with high unmet medical needs such as glioblastoma, pancreatic cancer, and hepatocellular carcinoma. The present review summarizes the past and current experiences with different pharmacological treatments that enabled galunisertib to be investigated in patients.

Transcriptome and proteome characterization of surface ectoderm cells differentiated from human iPSCs

“…To rule out potential off-target effects of the inhibitors, we further tested another two TGFβ-R inhibitors: LY215729950 (a TGFβ-RI inhibitor) and LY210976151 (a dual inhibitor targeting TGFβ-RI and TGFβ-RII) in inducing SE differentiation from hiPSCs. Similar to SB431542, adding LY2157299 did not change the SE morphologies (Supplementary Fig.…”

Berberine Suppresses Cell Motility Through Downregulation of TGF-β1 in Triple Negative Breast Cancer Cells

“…Because of the wide variety of effects of TGF-β on tumorigenesis, many TGF-β signaling antagonist agents to suppress TGF-β and its signaling pathway are under development at both the pre-clinical and clinical stages [29]. In breast cancer models with bone metastases, combined treatment with TGF-β antagonists and doxorubicin results in increased therapeutic efficacy and reduced dosage of chemotherapeutics [30].…”

Inhibition of S-Adenosylmethionine-Dependent Methyltransferase Attenuates TGFβ1-Induced EMT and Metastasis in Pancreatic Cancer: Putative Roles of miR-663a and miR-4787-5p

“…While a few remain in phase I and II clinical trial evaluations, unfortunately, many of them have already been terminated due to low efficacies or high toxicities (5). So far, LY2157299, a small molecule inhibitor of TGFBR1, is the most advanced TGF-β signaling inhibitor currently under clinical development (5, 51). The approach used in this study provides a new direction for investigating small molecule inhibitors of TGF-β signaling in PDAC via microRNA reprogramming of cancer cells.…”