ABSTRACT
Toll-like receptors (TLRs) play key role in innate immune response to Damage Associated Molecular Patterns (DAMPs) and Pathogen Associated Molecular Patterns (PAMPs). DAMP/PAMP-mediated activation of TLRs triggers NFκB signaling resulting in pro-inflammatory cytokine release. Using TLR2-Pam2CSK4 agonist co-crystal structure information, we designed and synthesized a novel series of Toll-like Receptor 2 (TLR2) lipid antagonists and identified compounds 14, 15 and 17 with sub-micromolar potency. TLR2 antagonists that we identified are stable forâ¯>â¯1.0â¯h in both gastric juice and PBS buffer and could be used as research tools.
Subject(s)
Lipids/chemistry , Oligopeptides/chemistry , Toll-Like Receptor 2/agonists , Toll-Like Receptor 2/antagonists & inhibitors , Toll-Like Receptor 9/agonists , Crystallization , Cytokines/metabolism , Drug Discovery , Humans , NF-kappa B/metabolism , Protein Binding , Signal Transduction , Structure-Activity Relationship , Toll-Like Receptor 2/chemistry , Toll-Like Receptor 9/chemistryABSTRACT
Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
