ABSTRACT
RIP1 regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP1 kinase that are suitable for advancement into the clinic have yet to be described. Herein, we report our lead optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and profile of clinical candidate GSK2982772 (compound 5), currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis. Compound 5 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking many TNF-dependent cellular responses. Highlighting its potential as a novel anti-inflammatory agent, the inhibitor was also able to reduce spontaneous production of cytokines from human ulcerative colitis explants. The highly favorable physicochemical and ADMET properties of 5, combined with high potency, led to a predicted low oral dose in humans.
Subject(s)
Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Colitis, Ulcerative/drug therapy , Inflammation/drug therapy , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Receptor-Interacting Protein Serine-Threonine Kinases/antagonists & inhibitors , Animals , Benzazepines/chemistry , Benzazepines/pharmacology , Colitis, Ulcerative/immunology , Cytokines/immunology , Dogs , Haplorhini , Humans , Inflammation/immunology , Mice , Molecular Docking Simulation , Rabbits , Rats , Receptor-Interacting Protein Serine-Threonine Kinases/immunology , Swine , Swine, Miniature , Tumor Necrosis Factor-alpha/immunologyABSTRACT
The recent discovery of the role of receptor interacting protein 1 (RIP1) kinase in tumor necrosis factor (TNF)-mediated inflammation has led to its emergence as a highly promising target for the treatment of multiple inflammatory diseases. We screened RIP1 against GSK's DNA-encoded small-molecule libraries and identified a novel highly potent benzoxazepinone inhibitor series. We demonstrate that this template possesses complete monokinase selectivity for RIP1 plus unique species selectivity for primate versus nonprimate RIP1. We elucidate the conformation of RIP1 bound to this benzoxazepinone inhibitor driving its high kinase selectivity and design specific mutations in murine RIP1 to restore potency to levels similar to primate RIP1. This series differentiates itself from known RIP1 inhibitors in combining high potency and kinase selectivity with good pharmacokinetic profiles in rodents. The favorable developability profile of this benzoxazepinone template, as exemplified by compound 14 (GSK'481), makes it an excellent starting point for further optimization into a RIP1 clinical candidate.
Subject(s)
DNA/chemistry , Isoxazoles/pharmacology , Oxazepines/pharmacology , Protein Kinase Inhibitors/pharmacology , Receptor-Interacting Protein Serine-Threonine Kinases/antagonists & inhibitors , Small Molecule Libraries/pharmacology , Animals , Cell Line, Tumor , Crystallography, X-Ray , Dose-Response Relationship, Drug , HT29 Cells , Humans , Isoxazoles/chemical synthesis , Isoxazoles/chemistry , Mice , Models, Molecular , Molecular Structure , Oxazepines/chemical synthesis , Oxazepines/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Structure-Activity Relationship , U937 CellsABSTRACT
Introduction of biological agents for the treatment of the chronic inflammatory joint disease rheumatoid arthritis has reinvigorated research into this debilitating disease. These agents have been shown to both act on the signs and symptoms of disease, as well as retard the progression of joint destruction. However, these agents are not efficacious in all cases and their expense and route of administration can severely limit their use. Therefore the search continues not only for additional targets to help those individuals refractive to current therapy but also for more affordable orally active small molecule alternatives to biological agents.
Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Cytokines/antagonists & inhibitors , Drug Delivery Systems , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Antirheumatic Agents/administration & dosage , Arthritis, Rheumatoid/etiology , Humans , MiceABSTRACT
Potent inhibitors of RIP1 kinase from three distinct series, 1-aminoisoquinolines, pyrrolo[2,3-b]pyridines, and furo[2,3-d]pyrimidines, all of the type II class recognizing a DLG-out inactive conformation, were identified from screening of our in-house kinase focused sets. An exemplar from the furo[2,3-d]pyrimidine series showed a dose proportional response in protection from hypothermia in a mouse model of TNFα induced lethal shock.