Heterobicyclic inhibitors of transforming growth factor beta receptor I (TGFβRI)

Publication date: Available online 31 January 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Lalgudi S. Harikrishnan, Jayakumar Warrier, Andrew J. Tebben, Gopikishan Tonukunuru, Sudhakara R. Madduri, Vishweshwaraiah Baligar, Raju Mannoori, Balaji Seshadri, Hasibur Rahaman, P.N. Arunachalam, Amol Dikundwar, Brian E. Fink, Joseph Fargnoli, Mark Fereshteh, Yi Fan, Jonathan Lippy, Ching-Ping Ho, Barri Wautlet, Steven Sheriff, Max Ruzanov, Robert M. Borzilleri
The TGFβ-TGFβR signaling pathway has been reported to play a protective role in the later stages of tumorigenesis via increasing immunosuppressive Treg cells and facilitating the epithelial to mesenchymal transition (EMT). Therefore, inhibition of TGFβR has the potential to enhance antitumor immunity. Herein we disclose the identification and optimization of novel heterobicyclic inhibitors of TGFβRI that demonstrate potent inhibition of SMAD phosphorylation. Application of structure-based drug design to the novel pyrrolotriazine chemotype resulted in improved binding affinity (Ki apparent = 0.14 nM), long residence time (T1/2 > 120 min) and significantly improved potency in the PSMAD cellular assay (IC50 = 24 nM). Several analogs inhibited phosphorylation of SMAD both in vitro and in vivo. Additionally, inhibition of TGFβ-stimulated phospho-SMAD was observed in primary human T cells.

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