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1.
Bioorg Med Chem Lett ; 26(22): 5403-5410, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27780639

RESUMO

The autotaxin-lysophosphatidic acid (ATX-LPA) axis has been implicated in several disease conditions including inflammation, fibrosis and cancer. This makes ATX an attractive drug target and its inhibition may lead to useful therapeutic agents. Through a high throughput screen (HTS) we identified a series of small molecule inhibitors of ATX which have subsequently been optimized for potency, selectivity and developability properties. This has delivered drug-like compounds such as 9v (CRT0273750) which modulate LPA levels in plasma and are suitable for in vivo studies. X-ray crystallography has revealed that these compounds have an unexpected binding mode in that they do not interact with the active site zinc ions but instead occupy the hydrophobic LPC pocket extending from the active site of ATX together with occupying the LPA 'exit' channel.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Lisofosfolipase/antagonistas & inibidores , Lisofosfolipídeos/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Cristalografia por Raios X , Inibidores Enzimáticos/farmacocinética , Humanos , Lisofosfolipase/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacologia
2.
Chem Sci ; 13(33): 9761-9773, 2022 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-36091903

RESUMO

The rise of antimicrobial resistance remains one of the greatest global health threats facing humanity. Furthermore, the development of novel antibiotics has all but ground to a halt due to a collision of intersectional pressures. Herein we determine the antimicrobial efficacy for 14 structurally related supramolecular self-associating amphiphiles against clinically relevant Gram-positive methicillin resistant Staphylococcus aureus and Gram-negative Escherichia coli. We establish the ability of these agents to selectively target phospholipid membranes of differing compositions, through a combination of computational host:guest complex formation simulations, synthetic vesicle lysis, adhesion and membrane fluidity experiments, alongside our novel 1H NMR CPMG nanodisc coordination assays, to verify a potential mode of action for this class of compounds and enable the production of evermore effective next-generation antimicrobial agents. Finally, we select a 7-compound subset, showing two lead compounds to exhibit 'druggable' profiles through completion of a variety of in vivo and in vitro DMPK studies.

3.
Cancer Discov ; 11(5): 1228-1247, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33328217

RESUMO

KRAS-mutant colorectal cancers are resistant to therapeutics, presenting a significant problem for ∼40% of cases. Rapalogs, which inhibit mTORC1 and thus protein synthesis, are significantly less potent in KRAS-mutant colorectal cancer. Using Kras-mutant mouse models and mouse- and patient-derived organoids, we demonstrate that KRAS with G12D mutation fundamentally rewires translation to increase both bulk and mRNA-specific translation initiation. This occurs via the MNK/eIF4E pathway culminating in sustained expression of c-MYC. By genetic and small-molecule targeting of this pathway, we acutely sensitize KRASG12D models to rapamycin via suppression of c-MYC. We show that 45% of colorectal cancers have high signaling through mTORC1 and the MNKs, with this signature correlating with a 3.5-year shorter cancer-specific survival in a subset of patients. This work provides a c-MYC-dependent cotargeting strategy with remarkable potency in multiple Kras-mutant mouse models and metastatic human organoids and identifies a patient population that may benefit from its clinical application. SIGNIFICANCE: KRAS mutation and elevated c-MYC are widespread in many tumors but remain predominantly untargetable. We find that mutant KRAS modulates translation, culminating in increased expression of c-MYC. We describe an effective strategy targeting mTORC1 and MNK in KRAS-mutant mouse and human models, pathways that are also commonly co-upregulated in colorectal cancer.This article is highlighted in the In This Issue feature, p. 995.


Assuntos
Neoplasias Colorretais/genética , Fator de Iniciação 4E em Eucariotos/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/efeitos dos fármacos , Inibidores de MTOR/farmacologia , Proteínas Serina-Treonina Quinases/efeitos dos fármacos , Animais , Neoplasias Colorretais/metabolismo , Modelos Animais de Doenças , Fator de Iniciação 4E em Eucariotos/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo
4.
J Med Chem ; 62(14): 6540-6560, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31199640

RESUMO

Tumors have evolved a variety of methods to reprogram conventional metabolic pathways to favor their own nutritional needs, including glutaminolysis, the first step of which is the hydrolysis of glutamine to glutamate by the amidohydrolase glutaminase 1 (GLS1). A GLS1 inhibitor could potentially target certain cancers by blocking the tumor cell's ability to produce glutamine-derived nutrients. Starting from the known GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide, we describe the medicinal chemistry evolution of a series from lipophilic inhibitors with suboptimal physicochemical and pharmacokinetic properties to cell potent examples with reduced molecular weight and lipophilicity, leading to compounds with greatly improved oral exposure that demonstrate in vivo target engagement accompanied by activity in relevant disease models.


Assuntos
Antineoplásicos/farmacologia , Glutaminase/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Piridazinas/farmacologia , Tiadiazóis/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Disponibilidade Biológica , Linhagem Celular Tumoral , Descoberta de Drogas , Glutaminase/metabolismo , Humanos , Masculino , Camundongos SCID , Simulação de Acoplamento Molecular , Neoplasias/metabolismo , Neoplasias/patologia , Piridazinas/química , Piridazinas/farmacocinética , Piridazinas/uso terapêutico , Tiadiazóis/química , Tiadiazóis/farmacocinética , Tiadiazóis/uso terapêutico
7.
J Med Chem ; 60(16): 6998-7011, 2017 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-28714688

RESUMO

The bromodomain and plant homeodomain finger-containing (BRPF) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Here, we describe NI-57 (16) as new pan-BRPF chemical probe of the bromodomain (BRD) of the BRPFs. Inhibitor 16 preferentially bound the BRD of BRPF1 and BRPF2 over BRPF3, whereas binding to BRD9 was weaker. Compound 16 has excellent selectivity over nonclass IV BRD proteins. Target engagement of BRPF1B and BRPF2 with 16 was demonstrated in nanoBRET and FRAP assays. The binding of 16 to BRPF1B was rationalized through an X-ray cocrystal structure determination, which showed a flipped binding orientation when compared to previous structures. We report studies that show 16 has functional activity in cellular assays by modulation of the phenotype at low micromolar concentrations in both cancer and inflammatory models. Pharmacokinetic data for 16 was generated in mouse with single dose administration showing favorable oral bioavailability.


Assuntos
Quinolonas/farmacologia , Sulfonamidas/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Linhagem Celular Tumoral , Proteínas de Ligação a DNA , Desenho de Fármacos , Estabilidade de Medicamentos , Meia-Vida , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Proteínas Nucleares/metabolismo , Domínios e Motivos de Interação entre Proteínas , Quinolonas/administração & dosagem , Quinolonas/síntese química , Quinolonas/farmacocinética , Relação Estrutura-Atividade , Sulfonamidas/administração & dosagem , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética
8.
J Med Chem ; 60(2): 668-680, 2017 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-28068087

RESUMO

The BRPF (bromodomain and PHD finger-containing) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Evaluation of the BRPF family as a potential drug target is at an early stage although there is an emerging understanding of a role in acute myeloid leukemia (AML). We report the optimization of fragment hit 5b to 13-d as a biased, potent inhibitor of the BRD of the BRPFs with excellent selectivity over nonclass IV BRD proteins. Evaluation of 13-d in a panel of cancer cell lines showed a selective inhibition of proliferation of a subset of AML lines. Pharmacokinetic studies established that 13-d had properties compatible with oral dosing in mouse models of disease (Fpo 49%). We propose that NI-42 (13-d) is a new chemical probe for the BRPFs suitable for cellular and in vivo studies to explore the fundamental biology of these proteins.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Antineoplásicos/farmacologia , Proteínas Nucleares/antagonistas & inibidores , Quinolonas/farmacologia , Sulfonamidas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Proteínas de Ligação a DNA , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Camundongos , Microssomos Hepáticos/metabolismo , Domínios Proteicos , Quinolonas/síntese química , Quinolonas/química , Quinolonas/farmacocinética , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacocinética
9.
J Med Chem ; 58(20): 8309-13, 2015 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-26356364

RESUMO

As part of a program to develop a small molecule inhibitor of LIMK, a series of aminothiazole inhibitors were discovered by high throughput screening. Scaffold hopping and subsequent SAR directed development led to a series of low nanomolar inhibitors of LIMK1 and LIMK2 that also inhibited the direct biomarker p-cofilin in cells and inhibited the invasion of MDA MB-231-luc cells in a matrigel inverse invasion assay.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Quinases Lim/antagonistas & inibidores , Tiazóis/síntese química , Tiazóis/farmacologia , Fatores de Despolimerização de Actina/metabolismo , Animais , Biotransformação , Desenho de Fármacos , Ensaios de Triagem em Larga Escala , Humanos , Microssomos Hepáticos/metabolismo , Invasividade Neoplásica , Relação Estrutura-Atividade
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