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1.
Bioorg Med Chem Lett ; 29(12): 1497-1501, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-31000154

RESUMO

Receptor-interacting protein kinase 1 (RIPK1), a key component of the cellular necroptosis pathway, has gained recognition as an important therapeutic target. Pharmacologic inhibition or genetic inactivation of RIPK1 has shown promise in animal models of disease ranging from acute ischemic conditions, chronic inflammation, and neurodegeneration. We present here a class of RIPK1 inhibitors that is distinguished by a lack of a lipophilic aromatic group present in most literature inhibitors that typically occupies a hydrophobic back pocket of the protein active site. Despite not having this ubiquitous feature of many known RIPK1 inhibitors, we were able to obtain compounds with good potency, kinase selectivity, and pharmacokinetic properties in rats. The use of the lipophilic yet metabolically stable pentafluoroethyl group was critical to balancing the potency and properties of optimized analogs.


Assuntos
Proteínas Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Humanos , Necrose , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Relação Estrutura-Atividade
2.
Bioorg Med Chem Lett ; 27(13): 2974-2981, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28512031

RESUMO

A high-throughput screening (HTS) of the Genentech/Roche library identified a novel, uncharged scaffold as a KDM5A inhibitor. Lacking insight into the binding mode, initial attempts to improve inhibitor potency failed to improve potency, and synthesis of analogs was further hampered by the presence of a C-C bond between the pyrrolidine and pyridine. Replacing this with a C-N bond significantly simplified synthesis, yielding pyrazole analog 35, of which we obtained a co-crystal structure with KDM5A. Using structure-based design approach, we identified 50 with improved biochemical, cell potency and reduced MW and lower lipophilicity (LogD) compared with the original hit. Furthermore, 50 showed lower clearance than 9 in mice. In combination with its remarkably low plasma protein binding (PPB) in mice (40%), oral dosing of 50 at 5mg/kg resulted in unbound Cmax ∼2-fold of its cell potency (PC9 H3K4Me3 0.96µM), meeting our criteria for an in vivo tool compound from a new scaffold.


Assuntos
Inibidores Enzimáticos/farmacologia , Ensaios de Triagem em Larga Escala , Pirazóis/farmacologia , Proteína 2 de Ligação ao Retinoblastoma/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Humanos , Camundongos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazóis/administração & dosagem , Pirazóis/química , Ratos , Proteína 2 de Ligação ao Retinoblastoma/metabolismo , Relação Estrutura-Atividade
3.
Bioorg Med Chem Lett ; 23(3): 907-11, 2013 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-23266122

RESUMO

A novel series of potent benzoxazole mPGES-1 inhibitors has been derived from a hit from a high throughput screen. Compound 37 displays mPGES-1 inhibition in an enzyme assay (0.018 µM) and PGE-2 inhibition in a cell-based assay (0.034 µM). It demonstrates 500- and 2500-fold selectivity for mPGES-1 over COX-2 and 6-keto PGF-1α, respectively. In vivo PK studies in dogs demonstrate 55% oral bioavailability and an 7 h half-life.


Assuntos
Benzoxazóis/química , Inibidores Enzimáticos/química , Oxirredutases Intramoleculares/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Amidas/farmacologia , Animais , Benzoxazóis/síntese química , Benzoxazóis/farmacocinética , Benzoxazóis/farmacologia , Disponibilidade Biológica , Cães , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Prostaglandina-E Sintases , Relação Estrutura-Atividade
4.
Sci Transl Med ; 14(652): eabl5654, 2022 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-35857625

RESUMO

Dilated cardiomyopathy (DCM) is characterized by reduced cardiac output, as well as thinning and enlargement of left ventricular chambers. These characteristics eventually lead to heart failure. Current standards of care do not target the underlying molecular mechanisms associated with genetic forms of heart failure, driving a need to develop novel therapeutics for DCM. To identify candidate therapeutics, we developed an in vitro DCM model using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) deficient in B-cell lymphoma 2 (BCL2)-associated athanogene 3 (BAG3). With these BAG3-deficient iPSC-CMs, we identified cardioprotective drugs using a phenotypic screen and deep learning. From a library of 5500 bioactive compounds and siRNA validation, we found that inhibiting histone deacetylase 6 (HDAC6) was cardioprotective at the sarcomere level. We translated this finding to a BAG3 cardiomyocyte-knockout (BAG3cKO) mouse model of DCM, showing that inhibiting HDAC6 with two isoform-selective inhibitors (tubastatin A and a novel inhibitor TYA-018) protected heart function. In BAG3cKO and BAG3E455K mice, HDAC6 inhibitors improved left ventricular ejection fraction and reduced left ventricular diameter at diastole and systole. In BAG3cKO mice, TYA-018 protected against sarcomere damage and reduced Nppb expression. Based on integrated transcriptomics and proteomics and mitochondrial function analysis, TYA-018 also enhanced energetics in these mice by increasing expression of targets associated with fatty acid metabolism, protein metabolism, and oxidative phosphorylation. Our results demonstrate the power of combining iPSC-CMs with phenotypic screening and deep learning to accelerate drug discovery, and they support developing novel therapies that address underlying mechanisms associated with heart disease.


Assuntos
Cardiomiopatia Dilatada , Aprendizado Profundo , Insuficiência Cardíaca , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/tratamento farmacológico , Cardiomiopatia Dilatada/genética , Modelos Animais de Doenças , Insuficiência Cardíaca/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Camundongos , Miócitos Cardíacos/metabolismo , Volume Sistólico , Função Ventricular Esquerda
5.
J Med Chem ; 65(17): 11500-11512, 2022 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34779204

RESUMO

VPS34 is a class III phosphoinositide 3-kinase involved in endosomal trafficking and autophagosome formation. Inhibitors of VPS34 were believed to have value as anticancer agents, but genetic and pharmacological data suggest that sustained inhibition of VPS34 kinase activity may not be well tolerated. Here we disclose the identification of a novel series of dihydropyrazolopyrazinone compounds represented by compound 5 as potent, selective, and orally bioavailable VPS34 inhibitors through a structure-based design strategy. A water-interacting hydrogen bond acceptor within an appropriate distance to a hinge-binding element was found to afford significant VPS34 potency across chemical scaffolds. The selectivity of compound 5 over PIK family kinases arises from interactions between the hinge-binding element and the pseudo-gatekeeper residue Met682. As recent in vivo pharmacology data suggests that sustained inhibition of VPS34 kinase activity may not be tolerated, structure-activity relationships leading to VPS34 inhibition may be helpful for avoiding this target in other ATP-competitive kinase programs.


Assuntos
Antineoplásicos , Classe III de Fosfatidilinositol 3-Quinases , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Autofagia , Endossomos , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação
6.
Elife ; 102021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34338636

RESUMO

Drug-induced cardiotoxicity and hepatotoxicity are major causes of drug attrition. To decrease late-stage drug attrition, pharmaceutical and biotechnology industries need to establish biologically relevant models that use phenotypic screening to detect drug-induced toxicity in vitro. In this study, we sought to rapidly detect patterns of cardiotoxicity using high-content image analysis with deep learning and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). We screened a library of 1280 bioactive compounds and identified those with potential cardiotoxic liabilities in iPSC-CMs using a single-parameter score based on deep learning. Compounds demonstrating cardiotoxicity in iPSC-CMs included DNA intercalators, ion channel blockers, epidermal growth factor receptor, cyclin-dependent kinase, and multi-kinase inhibitors. We also screened a diverse library of molecules with unknown targets and identified chemical frameworks that show cardiotoxic signal in iPSC-CMs. By using this screening approach during target discovery and lead optimization, we can de-risk early-stage drug discovery. We show that the broad applicability of combining deep learning with iPSC technology is an effective way to interrogate cellular phenotypes and identify drugs that may protect against diseased phenotypes and deleterious mutations.


Assuntos
Cardiotoxicidade/etiologia , Aprendizado Profundo , Coração/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Miócitos Cardíacos/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos
7.
J Leukoc Biol ; 107(6): 941-952, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31985117

RESUMO

Receptor interacting protein kinase 1 (RIP1) is a critical effector of inflammatory responses and cell death activation. Cell death pathways regulated by RIP1 include caspase-dependent apoptosis and caspase-independent necroptosis. The kinase activity of RIP1 has been associated with a number of inflammatory, neurodegenerative, and oncogenic diseases. In this study, we use the RIP1 kinase inhibitor GNE684 to demonstrate that RIP1 inhibition can effectively block skin inflammation and immune cell infiltrates in livers of Sharpin mutant (Cpdm; chronic proliferative dermatitis) mice in an interventional setting, after disease onset. On the other hand, genetic inactivation of RIP1 (RIP1 KD) or ablation of RIP3 (RIP3 KO) or MLKL (MLKL KO) did not affect testicular pathology of aging male mice. Likewise, infection with vaccinia virus or with mouse gammaherpesvirus MHV68 resulted in similar viral clearance in wild-type, RIP1 KD, and RIP3 KO mice. In summary, this study highlights the benefits of inhibiting RIP1 in skin inflammation, as opposed to its lack of relevance for testicular longevity and the response to certain viral infections.


Assuntos
Dermatite/genética , Infecções por Herpesviridae/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Pele/imunologia , Vacínia/genética , Animais , Doença Crônica , Dermatite/imunologia , Dermatite/patologia , Dermatite/virologia , Modelos Animais de Doenças , Gammaherpesvirinae/imunologia , Gammaherpesvirinae/patogenicidade , Regulação da Expressão Gênica , Infecções por Herpesviridae/patologia , Infecções por Herpesviridae/virologia , Inflamação , Fígado/imunologia , Fígado/patologia , Fígado/virologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/deficiência , Proteínas Quinases/genética , Proteínas Quinases/imunologia , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Proteína Serina-Treonina Quinases de Interação com Receptores/deficiência , Proteína Serina-Treonina Quinases de Interação com Receptores/imunologia , Transdução de Sinais , Pele/patologia , Pele/virologia , Testículo/imunologia , Testículo/patologia , Testículo/virologia , Vacínia/imunologia , Vacínia/patologia , Vacínia/virologia , Vaccinia virus/imunologia , Vaccinia virus/patogenicidade , Replicação Viral/imunologia
8.
Cell Death Differ ; 27(1): 161-175, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31101885

RESUMO

The kinase RIP1 acts in multiple signaling pathways to regulate inflammatory responses and it can trigger both apoptosis and necroptosis. Its kinase activity has been implicated in a range of inflammatory, neurodegenerative, and oncogenic diseases. Here, we explore the effect of inhibiting RIP1 genetically, using knock-in mice that express catalytically inactive RIP1 D138N, or pharmacologically, using the murine-potent inhibitor GNE684. Inhibition of RIP1 reduced collagen antibody-induced arthritis, and prevented skin inflammation caused by mutation of Sharpin, or colitis caused by deletion of Nemo from intestinal epithelial cells. Conversely, inhibition of RIP1 had no effect on tumor growth or survival in pancreatic tumor models driven by mutant Kras, nor did it reduce lung metastases in a B16 melanoma model. Collectively, our data emphasize a role for the kinase activity of RIP1 in certain inflammatory disease models, but question its relevance to tumor progression and metastases.


Assuntos
Inflamação/enzimologia , Neoplasias/enzimologia , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Animais , Artrite/enzimologia , Morte Celular , Linhagem Celular , Linhagem Celular Tumoral , Colite/etiologia , Colite/prevenção & controle , Dermatite/enzimologia , Feminino , Técnicas de Introdução de Genes , Humanos , Ileíte/etiologia , Ileíte/prevenção & controle , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Melanoma Experimental/patologia , Camundongos , Metástase Neoplásica , Neoplasias Pancreáticas/patologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Ratos , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/fisiologia
9.
Bioorg Med Chem Lett ; 19(12): 3339-43, 2009 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-19435660

RESUMO

PC-1 (NPP-1) inhibitors may be useful as therapeutics for the treatment of CDDP (calcium pyrophosphate dehydrate) deposition disease and osteoarthritis. We have identified a series of potent quinazolin-4-piperidin-4-ethyl sulfamide PC-1 inhibitors. The series, however, suffers from high affinity binding to hERG potassium channels, which can cause drug-induced QT prolongation. We used a hERG homology model to identify potential key interactions between our compounds and hERG, and the information gained was used to design and prepare a series of quinazolin-4-piperidin-4-methyl sulfamides that retain PC-1 activity but lack binding affinity for hERG.


Assuntos
Piperidinas/farmacologia , Pirofosfatases/antagonistas & inibidores , Quinazolinas/farmacologia , Sulfonamidas/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/química , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Síndrome do QT Longo , Osteoartrite/tratamento farmacológico , Diester Fosfórico Hidrolases , Piperidinas/química , Ligação Proteica , Quinazolinas/química , Sulfonamidas/química
11.
J Med Chem ; 60(19): 8083-8102, 2017 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-28929759

RESUMO

Significant data exists to suggest that dual leucine zipper kinase (DLK, MAP3K12) is a conserved regulator of neuronal degeneration following neuronal injury and in chronic neurodegenerative disease. Consequently, there is considerable interest in the identification of DLK inhibitors with a profile compatible with development for these indications. Herein, we use structure-based drug design combined with a focus on CNS drug-like properties to generate compounds with superior kinase selectivity and metabolic stability as compared to previously disclosed DLK inhibitors. These compounds, exemplified by inhibitor 14, retain excellent CNS penetration and are well tolerated following multiple days of dosing at concentrations that exceed those required for DLK inhibition in the brain.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , MAP Quinase Quinase Quinases/antagonistas & inibidores , Precursor de Proteína beta-Amiloide/biossíntese , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Desenho de Fármacos , Humanos , Macaca fascicularis , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
12.
Sci Transl Med ; 9(403)2017 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-28814543

RESUMO

Hallmarks of chronic neurodegenerative disease include progressive synaptic loss and neuronal cell death, yet the cellular pathways that underlie these processes remain largely undefined. We provide evidence that dual leucine zipper kinase (DLK) is an essential regulator of the progressive neurodegeneration that occurs in amyotrophic lateral sclerosis and Alzheimer's disease. We demonstrate that DLK/c-Jun N-terminal kinase signaling was increased in mouse models and human patients with these disorders and that genetic deletion of DLK protected against axon degeneration, neuronal loss, and functional decline in vivo. Furthermore, pharmacological inhibition of DLK activity was sufficient to attenuate the neuronal stress response and to provide functional benefit even in the presence of ongoing disease. These findings demonstrate that pathological activation of DLK is a conserved mechanism that regulates neurodegeneration and suggest that DLK inhibition may be a potential approach to treat multiple neurodegenerative diseases.


Assuntos
Zíper de Leucina , MAP Quinase Quinase Quinases/metabolismo , Doenças Neurodegenerativas/enzimologia , Doenças Neurodegenerativas/patologia , Transdução de Sinais , Doença de Alzheimer/enzimologia , Doença de Alzheimer/patologia , Esclerose Lateral Amiotrófica/enzimologia , Esclerose Lateral Amiotrófica/patologia , Animais , Modelos Animais de Doenças , Deleção de Genes , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos Transgênicos , Neuroproteção , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Medula Espinal/enzimologia , Medula Espinal/patologia , Superóxido Dismutase/metabolismo
13.
J Med Chem ; 59(18): 8345-68, 2016 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-27541271

RESUMO

NAMPT inhibitors may show potential as therapeutics for oncology. Throughout our NAMPT inhibitor program, we found that exposed pyridines or related heterocyclic systems in the left-hand portion of the inhibitors are necessary pharmacophores for potent cellular NAMPT inhibition. However, when combined with a benzyl group in the center of the inhibitors, such pyridine-like moieties also led to consistent and potent inhibition of CYP2C9. In an attempt to reduce CYP2C9 inhibition, a parallel synthesis approach was used to identify central benzyl group replacements with increased Fsp3. A spirocyclic central motif was thus discovered that was combined with left-hand pyridines (or pyridine-like systems) to provide cellularly potent NAMPT inhibitors with minimal CYP2C9 inhibition. Further optimization of potency and ADME properties led to the discovery of compound 68, a highly potent NAMPT inhibitor with outstanding efficacy in a mouse tumor xenograft model and lacking measurable CYP2C9 inhibition at the concentrations tested.


Assuntos
Citocromo P-450 CYP2C9/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Inibidores do Citocromo P-450 CYP2C9/química , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Camundongos , Camundongos Nus , Modelos Moleculares , Neoplasias/tratamento farmacológico , Nicotinamida Fosforribosiltransferase/metabolismo , Piridinas/uso terapêutico
14.
J Med Chem ; 58(20): 8182-99, 2015 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-26431428

RESUMO

Recent data suggest that inhibition of dual leucine zipper kinase (DLK, MAP3K12) has therapeutic potential for treatment of a number of indications ranging from acute neuronal injury to chronic neurodegenerative disease. Thus, high demand exists for selective small molecule DLK inhibitors with favorable drug-like properties and good CNS penetration. Herein we describe a shape-based scaffold hopping approach to convert pyrimidine 1 to a pyrazole core with improved physicochemical properties. We also present the first crystal structures of DLK. By utilizing a combination of property and structure-based design, we identified inhibitor 11, a potent, selective, and brain-penetrant inhibitor of DLK with activity in an in vivo nerve injury model.


Assuntos
Encéfalo/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , MAP Quinase Quinase Quinases/antagonistas & inibidores , Animais , Barreira Hematoencefálica , Descoberta de Drogas , MAP Quinase Quinase 4/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Doenças Neurodegenerativas/tratamento farmacológico , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , Difração de Raios X
15.
J Med Chem ; 58(1): 401-18, 2015 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-25341110

RESUMO

Dual leucine zipper kinase (DLK, MAP3K12) was recently identified as an essential regulator of neuronal degeneration in multiple contexts. Here we describe the generation of potent and selective DLK inhibitors starting from a high-throughput screening hit. Using proposed hinge-binding interactions to infer a binding mode and specific design parameters to optimize for CNS druglike molecules, we came to focus on the di(pyridin-2-yl)amines because of their combination of desirable potency and good brain penetration following oral dosing. Our lead inhibitor GNE-3511 (26) displayed concentration-dependent protection of neurons from degeneration in vitro and demonstrated dose-dependent activity in two different animal models of disease. These results suggest that specific pharmacological inhibition of DLK may have therapeutic potential in multiple indications.


Assuntos
MAP Quinase Quinase Quinases/antagonistas & inibidores , Degeneração Neural/prevenção & controle , Doenças Neurodegenerativas/prevenção & controle , Inibidores de Proteínas Quinases/farmacologia , Animais , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Descoberta de Drogas , Células HEK293 , Humanos , Células Madin Darby de Rim Canino , Camundongos Endogâmicos C57BL , Modelos Químicos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Ratos
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