Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Eur J Med Chem ; 258: 115509, 2023 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-37343464

RESUMO

Acute myeloid leukaemia (AML) is an aggressive type of leukaemia with low rates of long-term survival. While the current standard of care is based on cytotoxic chemotherapy, a promising emerging approach is differentiation therapy. However, most current differentiating agents target specific mutations and are effective only in certain patient subtypes. To identify agents which may be effective in wider population cohorts, we performed a phenotypic screen with the myeloid marker CD11b and identified a compound series that was able to differentiate AML cell lines in vitro regardless of their mutation status. Structure-activity relationship studies revealed that replacing the formamide and catechol methyl ether groups with sulfonamide and indazole respectively improved the in vitro metabolic profile of the series while maintaining the differentiation profile in multiple cell lines. This optimisation exercise enabled progression of a lead compound to in vivo efficacy testing. Our work supports the promise of phenotypic screening to identify novel small molecules that induce differentiation in a wide range of AML subtypes.


Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular , Diferenciação Celular , Piridinas/farmacologia
2.
iScience ; 25(8): 104787, 2022 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-35992086

RESUMO

Despite much progress in developing better drugs, many patients with acute myeloid leukemia (AML) still die within a year of diagnosis. This is partly because it is difficult to identify therapeutic targets that are effective across multiple AML subtypes. One common factor across AML subtypes is the presence of a block in differentiation. Overcoming this block should allow for the identification of therapies that are not dependent on a specific mutation for their efficacy. Here, we used a phenotypic screen to identify compounds that stimulate differentiation in genetically diverse AML cell lines. Lead compounds were shown to decrease tumor burden and to increase survival in vivo. Using multiple complementary target deconvolution approaches, these compounds were revealed to be anti-mitotic tubulin disruptors that cause differentiation by inducing a G2-M mitotic arrest. Together, these results reveal a function for tubulin disruptors in causing differentiation of AML cells.

3.
J Med Chem ; 64(21): 15608-15628, 2021 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-34672555

RESUMO

Induction of differentiation is a promising therapeutic strategy against acute myeloid leukemia. However, current differentiation therapies are effective only to specific patient populations. To identify novel differentiation agents with wider efficacy, we developed a phenotypic high-throughput screen with a range of genetically diverse cell lines. From the resulting hits, one chemical scaffold was optimized in terms of activity and physicochemical properties to yield OXS007417, a proof-of-concept tool compound, which was also able to decrease tumor volume in a murine in vivo xenograft model.


Assuntos
Antineoplásicos/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Fenótipo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...