ABSTRACT
Bruton's tyrosine kinase (BTK) inhibitors such as ibrutinib hold a prominent role in the treatment of B cell malignancies. However, further refinement is needed to this class of agents, particularly in terms of adverse events (potentially driven by kinase promiscuity), which preclude their evaluation in nononcology indications. Here, we report the discovery and preclinical characterization of evobrutinib, a potent, obligate covalent inhibitor with high kinase selectivity. Evobrutinib displayed sufficient preclinical pharmacokinetic and pharmacodynamic characteristics which allowed for in vivo evaluation in efficacy models. Moreover, the high selectivity of evobrutinib for BTK over epidermal growth factor receptor and other Tec family kinases suggested a low potential for off-target related adverse effects. Clinical investigation of evobrutinib is ongoing in several autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus.
Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Drug Discovery , Immune System Diseases/drug therapy , Piperidines/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Administration, Oral , Agammaglobulinaemia Tyrosine Kinase/metabolism , Dose-Response Relationship, Drug , Humans , Immune System Diseases/metabolism , Molecular Structure , Piperidines/administration & dosage , Piperidines/chemistry , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Pyrimidines/administration & dosage , Pyrimidines/chemistry , Structure-Activity RelationshipABSTRACT
SF0166, a small-molecule αvß3 antagonist, has physiochemical properties that allow distribution to the posterior segment of the eye after topical administration in an ophthalmic solution. The pharmacodynamics and ocular distribution of SF0166 were evaluated in several cell lines, chick chorioallantoic membrane assays, and models of ocular neovascularization in mice and pigmented rabbits. SF0166 inhibited cellular adhesion to vitronectin across human, rat, rabbit, and dog cell lines with IC50 values of 7.6 pM to 76 nM. SF0166 inhibited integrin-ligand interactions at IC50 values of 0.6-13 nM for human αvß3, αvß6, and αvß8 SF0166 significantly decreased neovascularization in the oxygen-induced retinopathy mouse model. SF0166 distributed to the choroid and retina after topical ocular administration in amounts that substantially exceeded the cellular IC50 for adhesion to vitronectin; drug concentrations were maintained for >12 hours. In the laser-induced choroidal neovascularization model, topical ocular administration of SF0166 decreased lesion area compared with vehicle and was comparable to a bevacizumab injection. In the vascular endothelial growth factor-induced early neovascularization and vascular leakage model, topical ocular application of SF0166 resulted in a dose-dependent reduction in vascular leakage; the highest ocular doses tested showed comparable activity to a bevacizumab injection.
Subject(s)
Eye/drug effects , Eye/metabolism , Integrin alphaVbeta3/antagonists & inhibitors , Propionates/administration & dosage , Propionates/pharmacology , Retinal Diseases/drug therapy , Administration, Topical , Animals , Cell Line , Eye/blood supply , Humans , Neovascularization, Pathologic/drug therapy , Propionates/metabolism , Propionates/therapeutic useABSTRACT
Several potent Aurora kinase inhibitors derived from 5H-benzo[c][1,8]naphthyridin-6-one scaffold were identified. A crystal structure of Aurora kinase A in complex with an initial hit revealed a binding mode of the inhibitor within the ATP binding site and provided insight for structure-guided compound optimization. Subsequent SAR campaign provided a potent and selective pan Aurora inhibitor, which demonstrated potent target modulation and antiproliferative effects in the pancreatic cell line, MIAPaCa-2. Furthermore, this compound inhibited phosphorylation of histone H3 (pHH3) in mouse bone morrow upon oral administration, which is consistent with inhibition of Aurora kinase B activity.
Subject(s)
Aurora Kinases/antagonists & inhibitors , Naphthyridines/pharmacology , Protein Kinase Inhibitors/pharmacology , Administration, Oral , Animals , Aurora Kinases/metabolism , Cell Line, Tumor , Crystallography, X-Ray , Dose-Response Relationship, Drug , Histones/antagonists & inhibitors , Histones/metabolism , Humans , Mice , Models, Molecular , Molecular Structure , Naphthyridines/administration & dosage , Naphthyridines/chemical synthesis , Phosphorylation/drug effects , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemical synthesis , Structure-Activity RelationshipABSTRACT
A series of 2-anilinothiazolones were prepared as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). The most potent compounds contained a 2-chloro or 2-fluoro group on the aniline ring with an isopropyl substituent on the 5-position of the thiazolone ring (compounds 2 and 3, respectively). The binding mode was determined through the X-ray co-crystal structure of the enzyme with compound 3. This compound was also approximately 70-fold selective over 11beta-HSD2 and was orally bioavailable in rat pharmacokinetic studies. However, compound 3 was >580-fold less active in the 11beta-HSD1 cell assay when tested in the presence of 3% human serum albumin.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Thiazoles/chemistry , Thiazoles/pharmacology , 11-beta-Hydroxysteroid Dehydrogenase Type 1/chemistry , Animals , CHO Cells , Chlorine/chemistry , Cricetinae , Cricetulus , Crystallography, X-Ray , Fluorine/chemistry , Humans , Molecular Structure , Rats , Structure-Activity Relationship , Thiazoles/classificationABSTRACT
In eukaryotic cells, cyclin-dependent kinase (CDK) complexes regulate the temporal progression of cells through the cell cycle. Deregulation in the cell cycle is an essential component in the evolution of cancer. Here, we validate CDK1 and CDK2 as potential therapeutic targets using novel selective small-molecule inhibitors of cyclin B1/CDK1 and cyclin E2/CDK2 enzyme complexes (CDKi). Flow cytometry-based methods were developed to assess intracellular retinoblastoma (Rb) phosphorylation to show inhibition of the CDK pathway. Tumor cells treated with CDK inhibitors showed an overall decrease in cell proliferation, accumulation of cells in G1 and G2, and apoptosis in a cell line-specific manner. Although CDK inhibitors activate p53, the inhibitors were equipotent in arresting the cell cycle in isogenic breast and colon tumor cells lacking p53, suggesting the response is independent of p53. In vivo, the CDK inhibitors prevented the growth of colon and prostate tumors, blocked proliferation of tumor cells, and inhibited Rb phosphorylation. The discovery and evaluation of novel potent and selective CDK1 and CDK2 inhibitors will help delineate the role that CDK complexes play in regulating tumorigenesis.
Subject(s)
CDC2 Protein Kinase/antagonists & inhibitors , Cyclin-Dependent Kinase 2/antagonists & inhibitors , Neoplasms/drug therapy , Neoplasms/enzymology , Protein Kinase Inhibitors/pharmacology , Animals , Apoptosis/drug effects , CDC2 Protein Kinase/metabolism , Cell Growth Processes/drug effects , Cell Growth Processes/physiology , Cell Line, Tumor , Cyclin B/antagonists & inhibitors , Cyclin B/metabolism , Cyclin B1 , Cyclin E/antagonists & inhibitors , Cyclin E/metabolism , Cyclin-Dependent Kinase 2/metabolism , Female , G1 Phase/drug effects , G2 Phase/drug effects , Humans , Mice , Mice, Nude , Neoplasms/pathology , Phosphorylation/drug effects , Retinoblastoma Protein/metabolism , Xenograft Model Antitumor AssaysABSTRACT
A series of alphaVbeta3 receptor antagonists lacking the amide bond of previously-reported 'chain-shortened' compounds is described. Replacement of the lone amide bond with two methylene groups in this series yields more lipophilic compounds that have longer half-lives, lower clearance, and greater oral bioavailability when administered to dogs.
Subject(s)
Benzenesulfonates/chemistry , Benzenesulfonates/pharmacokinetics , Integrin alphaVbeta3/antagonists & inhibitors , Iodobenzenes/chemistry , Iodobenzenes/pharmacokinetics , Animals , Dogs , Humans , Integrin alphaVbeta3/metabolismABSTRACT
3-(S)-Pyrimidin-5-yl-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5e) and 3-(S)-(methylpyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5f) were identified as potent and selective antagonists of the alpha(v)beta(3) receptor. These compounds have excellent in vitro profiles (IC(50) = 0.07 and 0.08 nM, respectively), significant unbound fractions in human plasma (6 and 4%), and good pharmacokinetics in rat, dog, and rhesus monkey. On the basis of the efficacy shown in an in vivo model of bone turnover following once-daily oral administration, these two compounds were selected for clinical development for the treatment of osteoporosis.
Subject(s)
Integrins/antagonists & inhibitors , Naphthyridines/pharmacology , Osteoporosis/drug therapy , Receptors, Vitronectin/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Bone Density/drug effects , Bone Resorption/drug therapy , Dogs , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Female , Humans , Inhibitory Concentration 50 , Integrins/metabolism , Macaca mulatta , Models, Molecular , Naphthyridines/chemistry , Naphthyridines/pharmacokinetics , Osteoporosis/prevention & control , Ovariectomy , Rats , Rats, Sprague-Dawley , Receptors, Vitronectin/metabolism , Structure-Activity RelationshipABSTRACT
Potent non-peptidic alpha(v)beta(3) antagonists have been prepared where deletion of an amide bond from an earlier series of linear RGD-mimetics provides a novel series of chain-shortened alpha(v)beta(3) antagonists with significantly improved oral pharmacokinetics. These chain-shortened alpha(v)beta(3) antagonists represent structurally novel integrin inhibitors.
Subject(s)
Integrin alphaVbeta3/antagonists & inhibitors , Oligopeptides/pharmacokinetics , Administration, Oral , Animals , Biological Availability , Dogs , Half-Life , Inhibitory Concentration 50 , Metabolic Clearance Rate , Molecular Mimicry , Oligopeptides/administration & dosage , Oligopeptides/pharmacology , Structure-Activity RelationshipABSTRACT
Potent non-peptidic alpha(v)beta(3) antagonists have been prepared incorporating various beta-amino acids as aspartic acid mimetics. Modification of the beta-alanine 3-substituents alters the potency and physicochemical properties of these receptor antagonists and in some cases provides orally bioavailable alpha(v)beta(3) inhibitors.