Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Cancer Discov ; 13(11): 2339-2355, 2023 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-37682219

RESUMO

The protein phosphatase SHP2/PTPN11 has been reported to be a key modulator of proliferative pathways in a wide range of malignancies. Intriguingly, SHP2 has also been described as a critical regulator of the tumor microenvironment. Based on this evidence SHP2 is considered a multifaceted target in cancer, spurring the notion that the development of direct inhibitors of SHP2 would provide the twofold benefit of tumor intrinsic and extrinsic inhibition. In this review, we will discuss the role of SHP2 in cancer and the tumor microenvironment, and the clinical strategies in which SHP2 inhibitors are leveraged as combination agents to improve therapeutic response. SIGNIFICANCE: The SHP2 phosphatase functions as a pleiotropic factor, and its inhibition not only hinders tumor growth but also reshapes the tumor microenvironment. Although their single-agent activity may be limited, SHP2 inhibitors hold the potential of being key combination agents to enhance the depth and the durability of tumor response to therapy.


Assuntos
Neoplasias , Proteína Tirosina Fosfatase não Receptora Tipo 11 , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Microambiente Tumoral
2.
J Med Chem ; 66(19): 13384-13399, 2023 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-37774359

RESUMO

Protein tyrosine phosphatase SHP2 mediates RAS-driven MAPK signaling and has emerged in recent years as a target of interest in oncology, both for treating with a single agent and in combination with a KRAS inhibitor. We were drawn to the pharmacological potential of SHP2 inhibition, especially following the initial observation that drug-like compounds could bind an allosteric site and enforce a closed, inactive state of the enzyme. Here, we describe the identification and characterization of GDC-1971 (formerly RLY-1971), a SHP2 inhibitor currently in clinical trials in combination with KRAS G12C inhibitor divarasib (GDC-6036) for the treatment of solid tumors driven by a KRAS G12C mutation.

3.
Org Lett ; 21(19): 8027-8030, 2019 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-31523969

RESUMO

Synthesis of the fused polycyclic ether motif comprising the EFG rings of the marine ladder polyethers tamulamides A and B has been achieved via two different etherification strategies. Ultimately, a reductive etherification approach proved most successful due to tolerance of the G ring substitution and provided the EFG 6,7,6 ring system in 58% yield.


Assuntos
Toxinas Marinhas/síntese química , Oxocinas/síntese química , Toxinas Marinhas/química , Conformação Molecular , Oxocinas/química , Estereoisomerismo
4.
Bioorg Med Chem ; 26(19): 5327-5335, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-29729986

RESUMO

Synthesis of the fused tetrahydrofuran motif comprising the ABC rings of the marine ladder polyethers tamulamides A and B has been achieved via two different polyepoxide cascade strategies. Investigations into a triepoxide cascade under aqueous conditions revealed the importance of the electronic nature of the cascade end-group with this initial approach. Ultimately, a diepoxide cascade under basic conditions proved most successful, providing the ABC tetrahydropyran triad in 41% yield.


Assuntos
Toxinas Marinhas/síntese química , Oxocinas/síntese química , Ciclização , Compostos de Epóxi/química , Furanos/química
5.
J Med Chem ; 59(13): 6501-11, 2016 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-27329786

RESUMO

The ERK/MAPK pathway plays a central role in the regulation of critical cellular processes and is activated in more than 30% of human cancers. Specific BRAF and MEK inhibitors have shown clinical efficacy in patients for the treatment of BRAF-mutant melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the ERK signal pathway. Acquired resistance to these agents has led to greater interest in ERK, a downstream target of the MAPK pathway. De novo design efforts of a novel scaffold derived from SCH772984 by employing hydrogen bond interactions specific for ERK in the binding pocket identified 1-(1H-pyrazolo[4,3-c]pyridin-6-yl)ureas as a viable lead series. Sequential SAR studies led to the identification of highly potent and selective ERK inhibitors with low molecular weight and high LE. Compound 21 exhibited potent target engagement and strong tumor regression in the BRAF(V600E) xenograft model.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Ureia/análogos & derivados , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade , Ureia/síntese química , Ureia/química , Ureia/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...