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

Jonathan M. Yingling, William T. McMillen, Lei Yan, Huocong Huang, J. Scott Sawyer, Jeremy Graff, David K. Clawson, Karen S. Britt, Bryan D. Anderson, Douglas W. Beight, Durisala Desaiah, Michael M. Lahn, Karim A. Benhadji, Maria J. Lallena, Rikke B. Holmgaard, Xiaohong Xu, Faming Zhang, Jason R. Manro, Philip W. Iversen, Chandrasekar V. IyerRolf A. Brekken, Michael D. Kalos, Kyla E. Driscoll

Research output: Contribution to journalArticlepeer-review

105 Scopus citations


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 antitumor 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 galunisertibdependent 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 antitumor 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.

Original languageEnglish (US)
Pages (from-to)6659-6677
Number of pages19
Issue number6
StatePublished - 2018


  • Galunisertib
  • LY2157299
  • SMAD
  • TGFβ receptor I

ASJC Scopus subject areas

  • Oncology


Dive into the research topics of 'Preclinical assessment of galunisertib (LY2157299 monohydrate), a first-in-class transforming growth factor-β receptor type I inhibitor'. Together they form a unique fingerprint.

Cite this