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

Autor: Harikrishnan LS; Department of Chemistry, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA. Electronic address: lalgudi.harikrishnan@bms.com., Warrier J; BBRC, Special Economic Zone, Biocon Park, Jigani Link Road, Bangalore, India., Tebben AJ; Molecular Structure & Design, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA., Tonukunuru G; BBRC, Special Economic Zone, Biocon Park, Jigani Link Road, Bangalore, India., Madduri SR; BBRC, Special Economic Zone, Biocon Park, Jigani Link Road, Bangalore, India., Baligar V; BBRC, Special Economic Zone, Biocon Park, Jigani Link Road, Bangalore, India., Mannoori R; BBRC, Special Economic Zone, Biocon Park, Jigani Link Road, Bangalore, India., Seshadri B; BBRC, Special Economic Zone, Biocon Park, Jigani Link Road, Bangalore, India., Rahaman H; BBRC, Special Economic Zone, Biocon Park, Jigani Link Road, Bangalore, India., Arunachalam PN; BBRC, Special Economic Zone, Biocon Park, Jigani Link Road, Bangalore, India., Dikundwar AG; BBRC, Special Economic Zone, Biocon Park, Jigani Link Road, Bangalore, India., Fink BE; Department of Chemistry, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA., Fargnoli J; Immuno-Oncology Small Molecule Biology, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA., Fereshteh M; Lead Discovery & Optimization, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA., Fan Y; Lead Discovery & Optimization, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA., Lippy J; Lead Discovery & Optimization, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA., Ho CP; Immuno-Oncology Small Molecule Biology, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA., Wautlet B; Immuno-Oncology Small Molecule Biology, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA., Sheriff S; Molecular Structure & Design, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA., Ruzanov M; Molecular Structure & Design, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA., Borzilleri RM; Department of Chemistry, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2018 Mar 01; Vol. 26 (5), pp. 1026-1034. Date of Electronic Publication: 2018 Jan 31.
DOI: 10.1016/j.bmc.2018.01.014
Abstrakt: 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 (IC 50  = 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.
(Copyright © 2018 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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