ABSTRACT
The TGFß-TGFßR 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 TGFßR has the potential to enhance antitumor immunity. Herein we disclose the identification and optimization of novel heterobicyclic inhibitors of TGFßRI that demonstrate potent inhibition of SMAD phosphorylation. Application of structure-based drug design to the novel pyrrolotriazine chemotype resulted in improved binding affinity (Ki apparentâ¯=â¯0.14â¯nM), long residence time (T1/2â¯>â¯120â¯min) and significantly improved potency in the PSMAD cellular assay (IC50â¯=â¯24â¯nM). Several analogs inhibited phosphorylation of SMAD both in vitro and in vivo. Additionally, inhibition of TGFß-stimulated phospho-SMAD was observed in primary human T cells.
Subject(s)
Bridged Bicyclo Compounds/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Binding Sites , Bridged Bicyclo Compounds/chemical synthesis , 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/metabolism , Protein Structure, Tertiary , Pyrroles/chemical synthesis , Pyrroles/chemistry , Pyrroles/metabolism , Receptor, Transforming Growth Factor-beta Type I , Receptors, Transforming Growth Factor beta/metabolism , Smad Proteins/metabolism , Structure-Activity Relationship , T-Lymphocytes/cytology , T-Lymphocytes/metabolism , Thiazines/chemical synthesis , Thiazines/chemistry , Thiazines/metabolismABSTRACT
JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile.
ABSTRACT
A series of 2-[2-(aroyl-aroxy)-methyl]-4-phenyl-1,3-thiazoles 4a-j were obtained via multiple step synthesis sequence beginning with the hydroxybenzophenones (1a-g). Hydroxybenzophenones on reaction with chloroacetonitrile affords [(2-benzoyl) phenoxy] acetonitrile (2a-g), which reacts with H(2)S/NH(4)OH and yields [(2-benzoyl) phenoxy] acetothiamide (3a-g), which on treatment with phenacylbromides affords 2-[2-(aroyl-aroxy)-methyl]-4-phenyl-1,3-thiazoles (4a-j). All the newly synthesized compounds were evaluated for their anti-inflammatory activity and were compared with standard drugs. Of the compounds studied, (4g), compounds with chloro substituents showed more potent activity than the standard drug phenyl butazone at all doses tested.
