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1.
Bioorg Med Chem ; 100: 117618, 2024 Feb 15.
Article in English | MEDLINE | ID: mdl-38309201

ABSTRACT

The virally encoded 3C-like protease (3CLpro) is a well-validated drug target for the inhibition of coronaviruses including Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Most inhibitors of 3CLpro are peptidomimetic, with a γ-lactam in place of Gln at the P1 position of the pseudopeptide chain. An effort was pursued to identify a viable alternative to the γ-lactam P1 mimetic which would improve physicochemical properties while retaining affinity for the target. Discovery of a 2-tetrahydrofuran as a suitable P1 replacement that is a potent enzymatic inhibitor of 3CLpro in SARS-CoV-2 virus is described herein.


Subject(s)
Antiviral Agents , Coronavirus Protease Inhibitors , Furans , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Lactams , Peptide Hydrolases , Protease Inhibitors/pharmacology , Protease Inhibitors/chemistry , SARS-CoV-2 , Furans/chemistry , Coronavirus Protease Inhibitors/chemistry
2.
Cell Chem Biol ; 29(6): 947-957.e8, 2022 06 16.
Article in English | MEDLINE | ID: mdl-35202587

ABSTRACT

In cystic fibrosis (CF), excessive furin activity plays a critical role in the activation of the epithelial sodium channel (ENaC), dysregulation of which contributes to airway dehydration, ineffective mucociliary clearance (MCC), and mucus obstruction. Here, we report a highly selective, cell-permeable furin inhibitor, BOS-318, that derives selectivity by eliciting the formation of a new, unexpected binding pocket independent of the active site catalytic triad. Using human ex vivo models, BOS-318 showed significant suppression of ENaC, which led to enhanced airway hydration and an ∼30-fold increase in MCC rate. Furin inhibition also protected ENaC from subsequent activation by neutrophil elastase, a soluble protease dominant in CF airways. Additional therapeutic benefits include protection against epithelial cell death induced by Pseudomonas aeruginosa exotoxin A. Our findings demonstrate the utility of selective furin inhibition as a mutation-agnostic approach that can correct features of CF airway pathophysiology in a manner expected to deliver therapeutic value.


Subject(s)
Cystic Fibrosis , Furin , Cystic Fibrosis/drug therapy , Cystic Fibrosis/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Epithelial Sodium Channels/genetics , Epithelial Sodium Channels/metabolism , Furin/antagonists & inhibitors , Humans , Mucociliary Clearance
3.
Chembiochem ; 22(3): 516-522, 2021 02 02.
Article in English | MEDLINE | ID: mdl-32974990

ABSTRACT

Indoleamine-2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that catalyzes the rate-limiting step in the kynurenine pathway of tryptophan (TRP) metabolism. As it is an inflammation-induced immunoregulatory enzyme, pharmacological inhibition of IDO1 activity is currently being pursued as a potential therapeutic tool for the treatment of cancer and other disease states. As such, a detailed understanding of the mechanism of action of IDO1 inhibitors with various mechanisms of inhibition is of great interest. Comparison of an apo-form-binding IDO1 inhibitor (GSK5628) to the heme-coordinating compound, epacadostat (Incyte), allows us to explore the details of the apo-binding inhibition of IDO1. Herein, we demonstrate that GSK5628 inhibits IDO1 by competing with heme for binding to a heme-free conformation of the enzyme (apo-IDO1), whereas epacadostat coordinates its binding with the iron atom of the IDO1 heme cofactor. Comparison of these two compounds in cellular systems reveals a long-lasting inhibitory effect of GSK5628, previously undescribed for other known IDO1 inhibitors. Detailed characterization of this apo-binding mechanism for IDO1 inhibition might help design superior inhibitors or could confer a unique competitive advantage over other IDO1 inhibitors vis-à-vis specificity and pharmacokinetic parameters.


Subject(s)
Enzyme Inhibitors/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Molecular Conformation
4.
Bioorg Med Chem ; 28(23): 115791, 2020 12 01.
Article in English | MEDLINE | ID: mdl-33059303

ABSTRACT

GlaxoSmithKline and Astex Pharmaceuticals recently disclosed the discovery of the potent H-PGDS inhibitor GSK2894631A 1a (IC50 = 9.9 nM) as part of a fragment-based drug discovery collaboration with Astex Pharmaceuticals. This molecule exhibited good murine pharmacokinetics, allowing it to be utilized to explore H-PGDS pharmacology in vivo. Yet, with prolonged dosing at higher concentrations, 1a induced CNS toxicity. Looking to attenuate brain penetration in this series, aza-quinolines, were prepared with the intent of increasing polar surface area. Nitrogen substitutions at the 6- and 8-positions of the quinoline were discovered to be tolerated by the enzyme. Subsequent structure activity studies in these aza-quinoline scaffolds led to the identification of 1,8-naphthyridine 1y (IC50 = 9.4 nM) as a potent peripherally restricted H-PGDS inhibitor. Compound 1y is efficacious in four in vivo inflammatory models and exhibits no CNS toxicity.


Subject(s)
Aza Compounds/chemistry , Enzyme Inhibitors/chemistry , Quinolines/chemistry , Animals , Binding Sites , Brain/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Crystallography, X-Ray , Drug Stability , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Humans , Intramolecular Oxidoreductases/antagonists & inhibitors , Intramolecular Oxidoreductases/metabolism , Kinetics , Male , Mice , Mice, Inbred C57BL , Molecular Dynamics Simulation , Muscle, Skeletal/chemistry , Muscle, Skeletal/metabolism , Rats , Structure-Activity Relationship
5.
Bioorg Med Chem Lett ; 29(19): 126604, 2019 10 01.
Article in English | MEDLINE | ID: mdl-31445854

ABSTRACT

This manuscript describes the discovery of a series of macrocyclic inhibitors of FXIa with oral bioavailability. Assisted by structure based drug design and ligand bound X-ray crystal structures, the group linking the P1 moiety to the macrocyclic core was modified with the goal of reducing H-bond donors to improve pharmacokinetic performance versus 9. This effort resulted in the discovery of several cyclic P1 linkers, exemplified by 10, that are constrained mimics of the bioactive conformation displayed by the acrylamide linker of 9. These cyclic P1 linkers demonstrated enhanced bioavailability and improved potency.


Subject(s)
Drug Design , Drug Discovery , Factor XIa/antagonists & inhibitors , Macrocyclic Compounds/administration & dosage , Macrocyclic Compounds/chemistry , Serine Proteinase Inhibitors/administration & dosage , Serine Proteinase Inhibitors/chemistry , Administration, Oral , Biological Availability , Humans , Ligands , Macrocyclic Compounds/pharmacology , Models, Molecular , Molecular Structure , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship
6.
Cell Chem Biol ; 26(9): 1322-1331.e4, 2019 09 19.
Article in English | MEDLINE | ID: mdl-31279605

ABSTRACT

Human cancers require fatty acid synthase (FASN)-dependent de novo long-chain fatty acid synthesis for proliferation. FASN is therefore an attractive drug target, but fast technologies for reliable label-free cellular compound profiling are lacking. Recently, MALDI-mass spectrometry (MALDI-MS) has emerged as an effective technology for discovery of recombinant protein target inhibitors. Here we present an automated, mechanistic MALDI-MS cell assay, which monitors accumulation of the FASN substrate, malonyl-coenzyme A (CoA), in whole cells with limited sample preparation. Profiling of inhibitors, including unpublished compounds, identified compound 1 as the most potent FASN inhibitor (1 nM in A549 cells) discovered to date. Moreover, cellular MALDI-MS assays enable parallel profiling of additional pathway metabolites. Surprisingly, several compounds triggered cytidine 5'-diphosphocholine (CDP-choline) but not malonyl-CoA accumulation indicating that they inhibit diacylglycerol generation but not FASN activity. Taken together, our study suggests that MALDI-MS cell assays may become important tools in drug profiling that provide additional mechanistic insights concerning compound action on metabolic pathways.


Subject(s)
Fatty Acid Synthases/antagonists & inhibitors , Fatty Acid Synthases/metabolism , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods , A549 Cells , Apoptosis/drug effects , Cell Line, Tumor , Drug Discovery/methods , Drug Evaluation, Preclinical/methods , Fatty Acid Synthase, Type I/antagonists & inhibitors , Fatty Acid Synthase, Type I/metabolism , Humans , Inhibitory Concentration 50 , K562 Cells , Lipogenesis , Malonyl Coenzyme A/metabolism , Proof of Concept Study
7.
ACS Med Chem Lett ; 10(6): 857-862, 2019 Jun 13.
Article in English | MEDLINE | ID: mdl-31223438

ABSTRACT

RIP1 regulates cell death and inflammation and is believed to play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases and cancer. While small-molecule inhibitors of RIP1 kinase have been advanced to the clinic for inflammatory diseases and CNS indications, RIP1 inhibitors for oncology indications have yet to be described. Herein we report on the discovery and profile of GSK3145095 (compound 6). Compound 6 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking RIP1 kinase-dependent cellular responses. Highlighting its potential as a novel cancer therapy, the inhibitor was also able to promote a tumor suppressive T cell phenotype in pancreatic adenocarcinoma organ cultures. Compound 6 is currently in phase 1 clinical studies for pancreatic adenocarcinoma and other selected solid tumors.

8.
Bioorg Med Chem ; 27(8): 1456-1478, 2019 04 15.
Article in English | MEDLINE | ID: mdl-30858025

ABSTRACT

With the goal of discovering more selective anti-inflammatory drugs, than COX inhibitors, to attenuate prostaglandin signaling, a fragment-based screen of hematopoietic prostaglandin D synthase was performed. The 76 crystallographic hits were sorted into similar groups, with the 3-cyano-quinoline 1a (FP IC50 = 220,000 nM, LE = 0.43) being a potent member of the 6,6-fused heterocyclic cluster. Employing SAR insights gained from structural comparisons of other H-PGDS fragment binding mode clusters, the initial hit 1a was converted into the 70-fold more potent quinoline 1d (IC50 = 3,100 nM, LE = 0.49). A systematic substitution of the amine moiety of 1d, utilizing structural information and array chemistry, with modifications to improve inhibitor stability, resulted in the identification of the 300-fold more active H-PGDS inhibitor tool compound 1bv (IC50 = 9.9 nM, LE = 0.42). This selective inhibitor exhibited good murine pharmacokinetics, dose-dependently attenuated PGD2 production in a mast cell degranulation assay and should be suitable to further explore H-PGDS biology.


Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Intramolecular Oxidoreductases/antagonists & inhibitors , Lipocalins/antagonists & inhibitors , Quinolines/chemistry , Quinolines/pharmacology , Animals , Drug Discovery , Enzyme Inhibitors/pharmacokinetics , Humans , Intramolecular Oxidoreductases/chemistry , Intramolecular Oxidoreductases/metabolism , Lipocalins/chemistry , Lipocalins/metabolism , Male , Mice, Inbred C57BL , Molecular Docking Simulation , Quinolines/pharmacokinetics
9.
ACS Med Chem Lett ; 9(7): 736-740, 2018 Jul 12.
Article in English | MEDLINE | ID: mdl-30034610

ABSTRACT

Bone Morphogenetic Protein 1 (BMP1) inhibition is a potential method for treating fibrosis because BMP1, a member of the zinc metalloprotease family, is required to convert pro-collagen to collagen. A novel class of reverse hydroxamate BMP1 inhibitors was discovered, and cocrystal structures with BMP1 were obtained. The observed binding mode is unique in that the small molecule occupies the nonprime side of the metalloprotease pocket providing an opportunity to build in metalloprotease selectivity. Structure-guided modification of the initial hit led to the identification of an oral in vivo tool compound with selectivity over other metalloproteases. Due to irreversible inhibition of cytochrome P450 3A4 for this chemical class, the risk of potential drug-drug interactions was managed by optimizing the series for subcutaneous injection.

10.
Bioorg Med Chem Lett ; 27(12): 2650-2654, 2017 06 15.
Article in English | MEDLINE | ID: mdl-28460818

ABSTRACT

Factor VIIa (FVIIa) inhibitors have shown strong antithrombotic efficacy in preclinical thrombosis models with limited bleeding liabilities. Discovery of potent, orally active FVIIa inhibitors has been largely unsuccessful due to the requirement of a basic P1 group to interact with Asp189 in the S1 binding pocket, limiting their membrane permeability. We have combined recently reported neutral P1 binding substituents with a highly optimized macrocyclic chemotype to produce FVIIa inhibitors with low nanomolar potency and enhanced permeability.


Subject(s)
Factor VIIa/antagonists & inhibitors , Macrocyclic Compounds/pharmacology , Serine Proteinase Inhibitors/pharmacology , Dose-Response Relationship, Drug , Humans , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/chemistry , Molecular Structure , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/chemistry , Structure-Activity Relationship
11.
J Med Chem ; 60(4): 1247-1261, 2017 02 23.
Article in English | MEDLINE | ID: mdl-28151659

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/immunology
12.
ACS Med Chem Lett ; 8(1): 67-72, 2017 Jan 12.
Article in English | MEDLINE | ID: mdl-28105277

ABSTRACT

Two novel series of meta-linked phenylglycine-based macrocyclic FVIIa inhibitors have been designed to improve the rodent metabolic stability and PK observed with the precursor para-linked phenylglycine macrocycles. Through iterative structure-based design and optimization, the TF/FVIIa Ki was improved to subnanomolar levels with good clotting activity, metabolic stability, and permeability.

13.
ACS Med Chem Lett ; 7(12): 1077-1081, 2016 Dec 08.
Article in English | MEDLINE | ID: mdl-27994741

ABSTRACT

Inhibitors of Factor VIIa (FVIIa), a serine protease in the clotting cascade, have shown strong antithrombotic efficacy in preclinical thrombosis models with minimal bleeding liabilities. Discovery of potent, orally active FVIIa inhibitors has been largely unsuccessful because known chemotypes have required a highly basic group in the S1 binding pocket for high affinity. A recently reported fragment screening effort resulted in the discovery of a neutral heterocycle, 7-chloro-3,4-dihydroisoquinolin-1(2H)-one, that binds in the S1 pocket of FVIIa and can be incorporated into a phenylglycine FVIIa inhibitor. Optimization of this P1 binding group led to the first series of neutral, permeable FVIIa inhibitors with low nanomolar potency.

14.
J Med Chem ; 59(15): 7125-37, 2016 08 11.
Article in English | MEDLINE | ID: mdl-27455395

ABSTRACT

Inhibitors of the tissue factor (TF)/factor VIIa complex (TF-FVIIa) are promising novel anticoagulants which show excellent efficacy and minimal bleeding in preclinical models. Starting with an aminoisoquinoline P1-based macrocyclic inhibitor, optimization of the P' groups led to a series of highly potent and selective TF-FVIIa inhibitors which displayed poor permeability. Fluorination of the aminoisoquinoline reduced the basicity of the P1 group and significantly improved permeability. The resulting lead compound was highly potent, selective, and achieved good pharmacokinetics in dogs with oral dosing. Moreover, it demonstrated robust antithrombotic activity in a rabbit model of arterial thrombosis.


Subject(s)
Anticoagulants/pharmacology , Drug Discovery , Factor VIIa/antagonists & inhibitors , Macrocyclic Compounds/pharmacology , Thromboplastin/antagonists & inhibitors , Administration, Oral , Animals , Anticoagulants/administration & dosage , Anticoagulants/chemistry , Biological Availability , Dogs , Dose-Response Relationship, Drug , Factor VIIa/metabolism , Healthy Volunteers , Humans , Macrocyclic Compounds/administration & dosage , Macrocyclic Compounds/chemistry , Male , Models, Molecular , Molecular Structure , Rabbits , Structure-Activity Relationship , Thromboplastin/metabolism
15.
Bioorg Med Chem ; 24(10): 2257-72, 2016 05 15.
Article in English | MEDLINE | ID: mdl-27073051

ABSTRACT

Pyridine-based Factor XIa (FXIa) inhibitor (S)-2 was optimized by modifying the P2 prime, P1, and scaffold regions. This work resulted in the discovery of the methyl N-phenyl carbamate P2 prime group which maintained FXIa activity, reduced the number of H-bond donors, and improved the physicochemical properties compared to the amino indazole P2 prime moiety. Compound (S)-17 was identified as a potent and selective FXIa inhibitor that was orally bioavailable. Replacement of the basic cyclohexyl methyl amine P1 in (S)-17 with the neutral p-chlorophenyltetrazole P1 resulted in the discovery of (S)-24 which showed a significant improvement in oral bioavailability compared to the previously reported imidazole (S)-23. Additional improvements in FXIa binding affinity, while maintaining oral bioavailability, was achieved by replacing the pyridine scaffold with either a regioisomeric pyridine or pyrimidine ring system.


Subject(s)
Anticoagulants/chemistry , Anticoagulants/pharmacology , Factor XIa/antagonists & inhibitors , Pyridines/chemistry , Pyridines/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Administration, Oral , Animals , Anticoagulants/administration & dosage , Anticoagulants/pharmacokinetics , Blood Coagulation/drug effects , Crystallography, X-Ray , Dogs , Factor XIa/metabolism , Humans , Models, Molecular , Phenylcarbamates/administration & dosage , Phenylcarbamates/chemistry , Phenylcarbamates/pharmacokinetics , Phenylcarbamates/pharmacology , Pyridines/administration & dosage , Pyridines/pharmacokinetics , Pyrimidines/administration & dosage , Pyrimidines/pharmacokinetics
16.
ACS Med Chem Lett ; 7(3): 217-22, 2016 Mar 10.
Article in English | MEDLINE | ID: mdl-26985301

ABSTRACT

A novel series of potent and selective hexokinase 2 (HK2) inhibitors, 2,6-disubstituted glucosamines, has been identified based on HTS hits, exemplified by compound 1. Inhibitor-bound crystal structures revealed that the HK2 enzyme could adopt an "induced-fit" conformation. The SAR study led to the identification of potent HK2 inhibitors, such as compound 34 with greater than 100-fold selectivity over HK1. Compound 25 inhibits in situ glycolysis in a UM-UC-3 bladder tumor cell line via (13)CNMR measurement of [3-(13)C]lactate produced from [1,6-(13)C2]glucose added to the cell culture.

17.
J Med Chem ; 59(5): 2163-78, 2016 Mar 10.
Article in English | MEDLINE | ID: mdl-26854747

ABSTRACT

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 Cells
18.
Bioorg Med Chem Lett ; 26(2): 472-478, 2016 Jan 15.
Article in English | MEDLINE | ID: mdl-26704266

ABSTRACT

The synthesis, structural activity relationships (SAR), and selectivity profile of a potent series of phenylalanine diamide FXIa inhibitors will be discussed. Exploration of P1 prime and P2 prime groups led to the discovery of compounds with high FXIa affinity, good potency in our clotting assay (aPPT), and high selectivity against a panel of relevant serine proteases as exemplified by compound 21. Compound 21 demonstrated good in vivo efficacy (EC50=2.8µM) in the rabbit electrically induced carotid arterial thrombosis model (ECAT).


Subject(s)
Anilides/pharmacology , Factor XIa/antagonists & inhibitors , Phenylalanine/analogs & derivatives , Phenylalanine/pharmacology , Anilides/chemical synthesis , Animals , Crystallography, X-Ray , Dogs , Phenylalanine/chemical synthesis , Rabbits , Structure-Activity Relationship
19.
Nat Chem Biol ; 11(11): 878-86, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26436839

ABSTRACT

Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are driver mutations in acute myeloid leukemia (AML) and other cancers. We report the development of new allosteric inhibitors of mutant IDH1. Crystallographic and biochemical results demonstrated that compounds of this chemical series bind to an allosteric site and lock the enzyme in a catalytically inactive conformation, thereby enabling inhibition of different clinically relevant IDH1 mutants. Treatment of IDH1 mutant primary AML cells uniformly led to a decrease in intracellular 2-HG, abrogation of the myeloid differentiation block and induction of granulocytic differentiation at the level of leukemic blasts and more immature stem-like cells, in vitro and in vivo. Molecularly, treatment with the inhibitors led to a reversal of the DNA cytosine hypermethylation patterns caused by mutant IDH1 in the cells of individuals with AML. Our study provides proof of concept for the molecular and biological activity of novel allosteric inhibitors for targeting different mutant forms of IDH1 in leukemia.


Subject(s)
Dihydropyridines/pharmacology , Enzyme Inhibitors/pharmacology , Isocitrate Dehydrogenase/antagonists & inhibitors , Leukemia, Myeloid, Acute/drug therapy , Pyrazoles/pharmacology , Allosteric Regulation , Allosteric Site , Animals , Cell Differentiation/drug effects , Cell Line, Tumor , CpG Islands , Crystallography, X-Ray , Cytosine/chemistry , Cytosine/metabolism , DNA Methylation/drug effects , Dihydropyridines/chemistry , Dihydropyridines/pharmacokinetics , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Granulocytes/drug effects , Granulocytes/enzymology , Granulocytes/pathology , Humans , Isocitrate Dehydrogenase/chemistry , Isocitrate Dehydrogenase/genetics , Isocitrate Dehydrogenase/metabolism , Kinetics , Leukemia, Myeloid, Acute/enzymology , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Male , Mice , Models, Molecular , Mutation , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/enzymology , Neoplastic Stem Cells/pathology , Primary Cell Culture , Protein Binding , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Xenograft Model Antitumor Assays
20.
J Thromb Thrombolysis ; 40(4): 416-23, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26249722

ABSTRACT

BMS-654457 ((+) 3'-(6-carbamimidoyl-4-methyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-2-yl)-4-carbamoyl-5'-(3-methyl-butyrylamino)-biphenyl-2-carboxylic acid) is a small-molecule factor XIa (FXIa) inhibitor. We evaluated the in vitro properties of BMS-654457 and its in vivo activities in rabbit models of electrolytic-induced carotid arterial thrombosis and cuticle bleeding time (BT). Kinetic studies conducted in vitro with a chromogenic substrate demonstrated that BMS-654457 is a reversible and competitive inhibitor for FXIa. BMS-654457 increased activated partial thromboplastin time (aPTT) without changing prothrombin time. It was equipotent in prolonging the plasma aPTT in human and rabbit, and less potent in rat and dog. It did not alter platelet aggregation to ADP, arachidonic acid and collagen. In vivo, BMS-654457 or vehicle was given IV prior to initiation of thrombosis or cuticle transection. Preservation of integrated carotid blood flow over 90 min (iCBF, % control) was used as a marker of antithrombotic efficacy. BMS-654457 at 0.37 mg/kg + 0.27 mg/kg/h produced almost 90 % preservation of iCBF compared to its vehicle (87 ± 10 and 16 ± 3 %, respectively, n = 6 per group) and increased BT by 1.2 ± 0.04-fold (P < 0.05). At a higher dose (1.1 mg/kg + 0.8 mg/kg/h), BMS-654457 increased BT by 1.33 ± 0.08-fold. This compares favorably to equivalent antithrombotic doses of reference anticoagulants (warfarin and dabigatran) and antiplatelet agents (clopidogrel and prasugrel) which produced four- to six-fold BT increases in the same model. In summary, BMS-654457 was effective in the prevention of arterial thrombosis in rabbits with limited effects on BT. This study supports inhibition of FXIa, with a small-molecule, reversible and direct inhibitor as a promising antithrombotic therapy with a wide therapeutic window.


Subject(s)
Factor XIa/antagonists & inhibitors , Fibrinolytic Agents/pharmacology , Thrombosis/drug therapy , Animals , Bleeding Time , Dogs , Fibrinolytic Agents/chemistry , Humans , Partial Thromboplastin Time , Rabbits , Rats , Species Specificity , Thrombosis/blood
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