RESUMEN
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.
Asunto(s)
Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Pirrolidinonas/farmacología , Quinasa Syk/antagonistas & inhibidores , Animales , Antineoplásicos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Pirimidinas/administración & dosificación , Pirimidinas/química , Pirrolidinonas/administración & dosificación , Pirrolidinonas/química , Relación Estructura-Actividad , Quinasa Syk/metabolismoRESUMEN
This publication details the successful use of FBDD (fragment-based drug discovery) principles in the invention of a novel covalent Bruton's tyrosine kinase inhibitor, which ultimately became the Takeda Pharmaceuticals clinical candidate TAK-020. Described herein are the discovery of the fragment 5-phenyl-2,4-dihydro-3H-1,2,4-triazol-3-one, the subsequent optimization of this hit molecule to the candidate, and synthesis and performance in pharmacodynamic and efficacy models along with direct biophysical comparison of TAK-020 with other clinical-level assets and the marketed drug Ibrutinib.
Asunto(s)
Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Artritis Experimental/tratamiento farmacológico , Diseño de Fármacos , Descubrimiento de Drogas/métodos , Inhibidores Enzimáticos/farmacología , Animales , Colágeno/toxicidad , Sistemas de Liberación de Medicamentos , Inhibidores Enzimáticos/química , Humanos , RatasAsunto(s)
Azoximetano/efectos adversos , Neoplasias Colorrectales/inmunología , Sulfato de Dextran/efectos adversos , Linfocitos Intraepiteliales/metabolismo , Receptores de Antígenos de Linfocitos T/genética , Animales , Neoplasias Colorrectales/inducido químicamente , Neoplasias Colorrectales/genética , Modelos Animales de Enfermedad , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , RatonesRESUMEN
The discovery and optimization of a series of 4-aminocinnoline-3-carboxamide inhibitors of Bruton's tyrosine kinase are reported. A fragment-based screening approach incorporating X-ray co-crystallography was used to identify a cinnoline fragment and characterize its binding mode in the ATP binding site of Btk. Optimization of the fragment hit resulted in the identification of a lead compound which reduced paw swelling in a dose- and exposure-dependent fashion in a rat model of collagen-induced arthritis.