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

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 G Dikundwar; Brian E Fink; Joseph Fargnoli; Mark Fereshteh; Yi Fan; Jonathan Lippy; Ching-Ping Ho; Barri Wautlet; Steven Sheriff; Max Ruzanov; Robert M Borzilleri

doi:10.1016/j.bmc.2018.01.014

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. Epub 2018 Jan 31.

Authors

Lalgudi S Harikrishnan¹, Jayakumar Warrier², Andrew J Tebben³, Gopikishan Tonukunuru², Sudhakara R Madduri², Vishweshwaraiah Baligar², Raju Mannoori², Balaji Seshadri², Hasibur Rahaman², P N Arunachalam², Amol G Dikundwar², Brian E Fink⁴, Joseph Fargnoli⁵, Mark Fereshteh⁶, Yi Fan⁶, Jonathan Lippy⁶, Ching-Ping Ho⁵, Barri Wautlet⁵, Steven Sheriff³, Max Ruzanov³, Robert M Borzilleri⁴

Affiliations

¹ Department of Chemistry, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA. Electronic address: lalgudi.harikrishnan@bms.com.
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 (T_1/2 > 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.

MeSH terms

Binding Sites
Bridged Bicyclo Compounds / chemical synthesis
Bridged Bicyclo Compounds / chemistry*
Bridged Bicyclo Compounds / pharmacology
Cells, Cultured
Crystallography, X-Ray
Drug Design
Epithelial-Mesenchymal Transition / drug effects
Humans
Molecular Dynamics Simulation
Phosphorylation
Protein Binding
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / metabolism
Protein Structure, Tertiary
Pyrroles / chemical synthesis
Pyrroles / chemistry
Pyrroles / metabolism
Receptor, Transforming Growth Factor-beta Type I
Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
Receptors, Transforming Growth Factor beta / metabolism
Smad Proteins / metabolism
Structure-Activity Relationship
T-Lymphocytes / cytology
T-Lymphocytes / metabolism
Thiazines / chemical synthesis
Thiazines / chemistry
Thiazines / metabolism

Substances

1H-pyrrolo(1,2-c)(1,3)thiazine
Bridged Bicyclo Compounds
Pyrroles
Receptors, Transforming Growth Factor beta
Smad Proteins
Thiazines
Protein Serine-Threonine Kinases
Receptor, Transforming Growth Factor-beta Type I