ABSTRACT
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.
Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Arthritis, Experimental/drug therapy , Drug Design , Drug Discovery/methods , Enzyme Inhibitors/pharmacology , Animals , Collagen/toxicity , Drug Delivery Systems , Enzyme Inhibitors/chemistry , Humans , RatsSubject(s)
Azoxymethane/adverse effects , Colorectal Neoplasms/immunology , Dextran Sulfate/adverse effects , Intraepithelial Lymphocytes/metabolism , Receptors, Antigen, T-Cell/genetics , Animals , Colorectal Neoplasms/chemically induced , Colorectal Neoplasms/genetics , Disease Models, Animal , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , MiceABSTRACT
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.
Subject(s)
Drug Discovery , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Pyrrolidinones/pharmacology , Syk Kinase/antagonists & inhibitors , Animals , Antineoplastic Agents , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Mice , Mice, Inbred C57BL , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Pyrimidines/administration & dosage , Pyrimidines/chemistry , Pyrrolidinones/administration & dosage , Pyrrolidinones/chemistry , Structure-Activity Relationship , Syk Kinase/metabolismABSTRACT
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.
