J. Scott Sawyer

Keywords: TGF-β, TGF-βRI kinase inhibitor, ALK5, galunisertib, LY2157299, cancer, clinical trials

Pyrazole-based inhibitors of the transforming growth factor-beta type I receptor kinase domain (TbetaR-I) are described. Examination of the SAR in both enzyme- and cell-based in vitro assays resulted in the emergence of two subseries featuring differing selectivity versus p38 MAP kinase. A common binding mode at the active site has been established by successful cocrystallization and X-ray analysis of potent inhibitors with the TbetaR-I receptor kinase domain.

// Jonathan M. Yingling 1 , William T. McMillen 2 , Lei Yan 2 , Huocong Huang 3 , J. Scott Sawyer 2 , Jeremy Graff 2 , David K. Clawson 2 , Karen S. Britt 2 , Bryan D. Anderson 2 , Douglas W. Beight 2 , Durisala Desaiah 2 , Michael M. Lahn 2 , Karim A. Benhadji 2 , Maria J. Lallena 2 , Rikke B. Holmgaard 2 , Xiaohong Xu 2 , Faming Zhang 2 , Jason R. Manro 2 , Philip W. Iversen 2 , Chandrasekar V. Iyer 2 , Rolf A. Brekken 3 , Michael D. Kalos 2 and Kyla E. Driscoll 2 1 Idera Pharmaceuticals, Inc., Cambridge, Massachusetts, USA 2 Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN and New York, NY, USA 3 Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA Correspondence to: Kyla E. Driscoll, email: // Keywords : TGFβ receptor I; SMAD; galunisertib; LY2157299 Received : September 28, 2017 Accepted : December 21, 2017 Published : December 31, 2017 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.