RESUMEN
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.
Asunto(s)
Lípidos/química , Oligopéptidos/química , Receptor Toll-Like 2/agonistas , Receptor Toll-Like 2/antagonistas & inhibidores , Receptor Toll-Like 9/agonistas , Cristalización , Citocinas/metabolismo , Descubrimiento de Drogas , Humanos , FN-kappa B/metabolismo , Unión Proteica , Transducción de Señal , Relación Estructura-Actividad , Receptor Toll-Like 2/química , Receptor Toll-Like 9/químicaRESUMEN
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.