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1.
J Pharmacol Exp Ther ; 388(3): 813-826, 2024 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-38336379

RESUMO

Systemic and cerebral inflammatory responses are implicated in the pathogenesis of obesity and associated metabolic impairment. While the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome has been linked to obesity-associated inflammation, whether it contributes to the development or maintenance of obesity is unknown. We provide support for a direct role of saturated fatty acids, such as palmitic acid, as NLRP3 activating stimuli in obese states. To investigate whether NLRP3 activation contributes to the pathogenesis of diet-induced obesity (DIO) in mice, we tested two different clinical-stage NLRP3 inflammasome inhibitors. We demonstrate a contributory role of this key inflammasome to established obesity and associated systemic and cerebral inflammation. By comparing their effects to calorie restriction, we aimed to identify specific NLRP3-sensitive mechanisms contributing to obesity-induced inflammation (as opposed to be those regulated by weight loss per se). In addition, a direct comparison of an NLRP3 inhibitor to a glucagon like peptide-1 receptor agonist, semaglutide (Wegovy), in the DIO model allowed an appreciation of the relative efficacy of these two therapeutic strategies on obesity, its associated systemic inflammatory response, and cerebral gliosis. We show that two structurally distinct, NLRP3 inhibitors, NT-0249 and NT-0796, reverse obesity in the DIO mouse model and that brain exposure appears necessary for efficacy. In support of this, we show that DIO-driven hypothalamic glial fibrillary acidic protein expression is blocked by dosing with NT-0249/NT-0796. While matching weight loss driven by semaglutide or calorie restriction, remarkably, NLRP3 inhibition provided enhanced improvements in disease-relevant biomarkers of acute phase response, cardiovascular inflammation, and lipid metabolism. SIGNIFICANCE STATEMENT: Obesity is a global health concern that predisposes individuals to chronic disease such as diabetes and cardiovascular disease at least in part by promoting systemic inflammation. We report that in mice fed a high-fat, obesogenic diet, obesity is reversed by either of two inhibitors of the intracellular inflammatory mediator NLRP3. Furthermore, NLRP3 inhibition reduces both hypothalamic gliosis and circulating biomarkers of cardiovascular disease risk beyond what can be achieved by either the glucagon like peptide-1 agonist semaglutide or calorie restriction alone.


Assuntos
Doenças Cardiovasculares , Inflamassomos , Camundongos , Animais , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Gliose/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos NOD , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Obesidade/metabolismo , Redução de Peso , Biomarcadores , Peptídeos Semelhantes ao Glucagon , Camundongos Endogâmicos C57BL
2.
J Med Chem ; 64(18): 13524-13539, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34478292

RESUMO

Inhibition of Mer and Axl kinases has been implicated as a potential way to improve the efficacy of current immuno-oncology therapeutics by restoring the innate immune response in the tumor microenvironment. Highly selective dual Mer/Axl kinase inhibitors are required to validate this hypothesis. Starting from hits from a DNA-encoded library screen, we optimized an imidazo[1,2-a]pyridine series using structure-based compound design to improve potency and reduce lipophilicity, resulting in a highly selective in vivo probe compound 32. We demonstrated dose-dependent in vivo efficacy and target engagement in Mer- and Axl-dependent efficacy models using two structurally differentiated and selective dual Mer/Axl inhibitors. Additionally, in vivo efficacy was observed in a preclinical MC38 immuno-oncology model in combination with anti-PD1 antibodies and ionizing radiation.


Assuntos
Antineoplásicos/uso terapêutico , Imidazóis/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Animais , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Imidazóis/síntese química , Masculino , Camundongos Endogâmicos C57BL , Camundongos Nus , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Proteínas Proto-Oncogênicas/metabolismo , Piridinas/síntese química , Receptores Proteína Tirosina Quinases/metabolismo , Relação Estrutura-Atividade , c-Mer Tirosina Quinase/metabolismo , Receptor Tirosina Quinase Axl
3.
Mol Cancer Ther ; 20(2): 238-249, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33273059

RESUMO

The RAS-regulated RAF-MEK1/2-ERK1/2 (RAS/MAPK) signaling pathway is a major driver in oncogenesis and is frequently dysregulated in human cancers, primarily by mutations in BRAF or RAS genes. The clinical benefit of inhibitors of this pathway as single agents has only been realized in BRAF-mutant melanoma, with limited effect of single-agent pathway inhibitors in KRAS-mutant tumors. Combined inhibition of multiple nodes within this pathway, such as MEK1/2 and ERK1/2, may be necessary to effectively suppress pathway signaling in KRAS-mutant tumors and achieve meaningful clinical benefit. Here, we report the discovery and characterization of AZD0364, a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and kinase selectivity. In vitro, AZD0364 treatment resulted in inhibition of proximal and distal biomarkers and reduced proliferation in sensitive BRAF-mutant and KRAS-mutant cell lines. In multiple in vivo xenograft models, AZD0364 showed dose- and time-dependent modulation of ERK1/2-dependent signaling biomarkers resulting in tumor regression in sensitive BRAF- and KRAS-mutant xenografts. We demonstrate that AZD0364 in combination with the MEK1/2 inhibitor, selumetinib (AZD6244 and ARRY142886), enhances efficacy in KRAS-mutant preclinical models that are moderately sensitive or resistant to MEK1/2 inhibition. This combination results in deeper and more durable suppression of the RAS/MAPK signaling pathway that is not achievable with single-agent treatment. The AZD0364 and selumetinib combination also results in significant tumor regressions in multiple KRAS-mutant xenograft models. The combination of ERK1/2 and MEK1/2 inhibition thereby represents a viable clinical approach to target KRAS-mutant tumors.


Assuntos
Benzimidazóis/uso terapêutico , Imidazóis/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Pirazinas/uso terapêutico , Pirimidinas/uso terapêutico , Animais , Benzimidazóis/farmacologia , Modelos Animais de Doenças , Humanos , Imidazóis/farmacologia , Camundongos , Camundongos Nus , Pirazinas/farmacologia , Pirimidinas/farmacologia
4.
J Med Chem ; 62(24): 11004-11018, 2019 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-31710489

RESUMO

The RAS/MAPK pathway is a major driver of oncogenesis and is dysregulated in approximately 30% of human cancers, primarily by mutations in the BRAF or RAS genes. The extracellular-signal-regulated kinases (ERK1 and ERK2) serve as central nodes within this pathway. The feasibility of targeting the RAS/MAPK pathway has been demonstrated by the clinical responses observed through the use of BRAF and MEK inhibitors in BRAF V600E/K metastatic melanoma; however, resistance frequently develops. Importantly, ERK1/2 inhibition may have clinical utility in overcoming acquired resistance to RAF and MEK inhibitors, where RAS/MAPK pathway reactivation has occurred, such as relapsed BRAF V600E/K melanoma. We describe our structure-based design approach leading to the discovery of AZD0364, a potent and selective inhibitor of ERK1 and ERK2. AZD0364 exhibits high cellular potency (IC50 = 6 nM) as well as excellent physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties and has demonstrated encouraging antitumor activity in preclinical models.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Descoberta de Drogas , Imidazóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/uso terapêutico , Pirimidinas/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Apoptose , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células , Quimioterapia Combinada , Feminino , Humanos , Imidazóis/farmacologia , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Estrutura Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Pirazinas/farmacologia , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
5.
J Med Chem ; 62(21): 9918-9930, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31622099

RESUMO

In this article, we report the discovery of a series of 5-azaquinazolines as selective IRAK4 inhibitors. From modestly potent quinazoline 4, we introduced a 5-aza substitution to mask the 4-NH hydrogen bond donor (HBD). This allowed us to substitute the core with a 2-aminopyrazole, which showed large gains in cellular potency despite the additional formal HBD. Further optimization led to 6-cyanomethyl-5-azaquinazoline 13, a selective IRAK4 inhibitor, which proved efficacious in combination with ibrutinib, while showing very little activity as a single agent up to 100 mg/kg. This contrasted to previously reported IRAK4 inhibitors that exhibited efficacy in the same model as single agents and was attributed to the enhanced specificity of 13 toward IRAK4.


Assuntos
Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Terapia de Alvo Molecular , Fator 88 de Diferenciação Mieloide/genética , Quinazolinas/química , Quinazolinas/farmacologia , Administração Oral , Animais , Linhagem Celular Tumoral , Desenho de Fármacos , Feminino , Humanos , Quinases Associadas a Receptores de Interleucina-1/química , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Camundongos , Modelos Moleculares , Mutação , Conformação Proteica , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/administração & dosagem , Quinazolinas/farmacocinética , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Bioorg Med Chem ; 26(4): 913-924, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29398441

RESUMO

We have developed a series of orally efficacious IRAK4 inhibitors, based on a scaffold hopping strategy and using rational structure based design. Efforts to tackle low permeability and high efflux in our previously reported pyrrolopyrimidine series (Scott et al., 2017) led to the identification of pyrrolotriazines which contained one less formal hydrogen bond donor and were intrinsically more lipophilic. Further optimisation of substituents on this pyrrolotriazine core culminated with the discovery of 30 as a promising in vivo probe to assess the potential of IRAK4 inhibition for the treatment of MyD88 mutant DLBCL in combination with a BTK inhibitor. When tested in an ABC-DLBCL model with a dual MyD88/CD79 mutation (OCI-LY10), 30 demonstrated tumour regressions in combination with ibrutinib.


Assuntos
Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Pirróis/química , Tiazinas/química , Animais , Sítios de Ligação , Células CACO-2 , Cães , Desenho de Fármacos , Meia-Vida , Hepatócitos/citologia , Hepatócitos/metabolismo , Humanos , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Simulação de Dinâmica Molecular , Mutação , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Permeabilidade/efeitos dos fármacos , Proteínas Quinases/química , Proteínas Quinases/metabolismo , Pirróis/farmacocinética , Pirróis/farmacologia , Ratos , Relação Estrutura-Atividade , Tiazinas/farmacocinética , Tiazinas/farmacologia
7.
J Med Chem ; 60(24): 10071-10091, 2017 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-29172502

RESUMO

Herein we report the optimization of a series of pyrrolopyrimidine inhibitors of interleukin-1 receptor associated kinase 4 (IRAK4) using X-ray crystal structures and structure based design to identify and optimize our scaffold. Compound 28 demonstrated a favorable physicochemical and kinase selectivity profile and was identified as a promising in vivo tool with which to explore the role of IRAK4 inhibition in the treatment of mutant MYD88L265P diffuse large B-cell lymphoma (DLBCL). Compound 28 was shown to be capable of demonstrating inhibition of NF-κB activation and growth of the ABC subtype of DLBCL cell lines in vitro at high concentrations but showed greater effects in combination with a BTK inhibitor at lower concentrations. In vivo, the combination of compound 28 and ibrutinib led to tumor regression in an ABC-DLBCL mouse model.


Assuntos
Antineoplásicos/farmacologia , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Cristalografia por Raios X , Cães , Feminino , Humanos , Quinases Associadas a Receptores de Interleucina-1/química , Linfoma Difuso de Grandes Células B/genética , Espectroscopia de Ressonância Magnética , Masculino , Camundongos SCID , Mutação , Fator 88 de Diferenciação Mieloide/genética , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/química , Pirróis/química , Ratos Wistar , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
8.
J Med Chem ; 60(8): 3438-3450, 2017 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-28376306

RESUMO

There are a number of small-molecule inhibitors targeting the RAS/RAF/MEK/ERK signaling pathway that have either been approved or are in clinical development for oncology across a range of disease indications. The inhibition of ERK1/2 is of significant current interest, as cell lines with acquired resistance to BRAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition in preclinical models. This article reports on our recent work to identify novel, potent, and selective reversible ERK1/2 inhibitors from a low-molecular-weight, modestly active, and highly promiscuous chemical start point, compound 4. To guide and inform the evolution of this series, inhibitor binding mode information from X-ray crystal structures was critical in the rapid exploration of this template to compound 35, which was active when tested in in vivo antitumor efficacy experiments.


Assuntos
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Cães , Descoberta de Drogas , Humanos , Metilação , Inibidores de Proteínas Quinases/farmacocinética
9.
Nat Chem Biol ; 12(6): 444-51, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27110679

RESUMO

Usher syndrome type III (USH3), characterized by progressive deafness, variable balance disorder and blindness, is caused by destabilizing mutations in the gene encoding the clarin-1 (CLRN1) protein. Here we report a new strategy to mitigate hearing loss associated with a common USH3 mutation CLRN1(N48K) that involves cell-based high-throughput screening of small molecules capable of stabilizing CLRN1(N48K), followed by a secondary screening to eliminate general proteasome inhibitors, and finally an iterative process to optimize structure-activity relationships. This resulted in the identification of BioFocus 844 (BF844). To test the efficacy of BF844, we developed a mouse model that mimicked the progressive hearing loss associated with USH3. BF844 effectively attenuated progressive hearing loss and prevented deafness in this model. Because the CLRN1(N48K) mutation causes both hearing and vision loss, BF844 could in principle prevent both sensory deficiencies in patients with USH3. Moreover, the strategy described here could help identify drugs for other protein-destabilizing monogenic disorders.


Assuntos
Modelos Animais de Doenças , Proteínas de Membrana/antagonistas & inibidores , Pirazóis/farmacologia , Piridazinas/farmacologia , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/uso terapêutico , Síndromes de Usher/tratamento farmacológico , Animais , Ensaios de Triagem em Larga Escala , Humanos , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Pirazóis/uso terapêutico , Piridazinas/síntese química , Piridazinas/química , Piridazinas/uso terapêutico , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , Síndromes de Usher/genética
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