2. Academic Validation
  3. Heterobicyclic inhibitors of transforming growth factor beta receptor I (TGFβRI)

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

  • Bioorg Med Chem. 2018 Mar 1;26(5):1026-1034. doi: 10.1016/j.bmc.2018.01.014.
Lalgudi S Harikrishnan 1,  Jayakumar Warrier 2,  Andrew J Tebben 3,  Gopikishan Tonukunuru 2,  Sudhakara R Madduri 2,  Vishweshwaraiah Baligar 2,  Raju Mannoori 2,  Balaji Seshadri 2,  Hasibur Rahaman 2,  P N Arunachalam 2,  Amol G Dikundwar 2,  Brian E Fink 4,  Joseph Fargnoli 5,  Mark Fereshteh 6,  Yi Fan 6,  Jonathan Lippy 6,  Ching-Ping Ho 5,  Barri Wautlet 5,  Steven Sheriff 3,  Max Ruzanov 3,  Robert M Borzilleri 4
Affiliations

Affiliations

  • 1 Department of Chemistry, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA. Electronic address: [email protected].
  • 2 BBRC, Special Economic Zone, Biocon Park, Jigani Link Road, Bangalore, India.
  • 3 Molecular Structure & Design, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA.
  • 4 Department of Chemistry, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA.
  • 5 Immuno-Oncology Small Molecule Biology, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA.
  • 6 Lead Discovery & Optimization, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA.
PMID: 29422332 DOI: 10.1016/j.bmc.2018.01.014
Abstract

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.

Keywords

ALK; TGF; TGF-beta; TGFBR; TGFβ.

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