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1.
ACS Chem Biol ; 16(11): 2185-2192, 2021 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-34515462

RESUMO

Bromodomain-containing proteins frequently reside in multisubunit chromatin complexes with tissue or cell state-specific compositions. Recent studies have revealed tumor-specific dependencies on the BAF complex bromodomain subunit BRD9 that are a result of recurrent mutations afflicting the structure and composition of associated complex members. To enable the study of ligand engaged complex assemblies, we established a chemoproteomics approach using a functionalized derivative of the BRD9 ligand BI-9564 as an affinity matrix. Unexpectedly, in addition to known interactions with BRD9 and associated BAF complex proteins, we identify a previously unreported interaction with members of the NuA4 complex through the bromodomain-containing subunit BRD8. We apply this finding, alongside a homology-model-guided design, to develop chemical biology approaches for the study of BRD8 inhibition and to arrive at first-in-class selective and cellularly active probes for BRD8. These tools will empower further pharmacological studies of BRD9 and BRD8 within respective BAF and NuA4 complexes.


Assuntos
Benzilaminas/farmacologia , Naftiridinas/farmacologia , Proteômica/métodos , Fatores de Transcrição/metabolismo , Linhagem Celular Tumoral , Linhagem da Célula , Reparo do DNA , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Ligantes , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Domínios Proteicos , Subunidades Proteicas , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Transcriptoma
3.
J Med Chem ; 58(18): 7195-216, 2015 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-26230873

RESUMO

While several therapeutic options exist, the need for more effective, safe, and convenient treatment for a variety of autoimmune diseases persists. Targeting the Janus tyrosine kinases (JAKs), which play essential roles in cell signaling responses and can contribute to aberrant immune function associated with disease, has emerged as a novel and attractive approach for the development of new autoimmune disease therapies. We screened our compound library against JAK3, a key signaling kinase in immune cells, and identified multiple scaffolds showing good inhibitory activity for this kinase. A particular scaffold of interest, the 1H-pyrrolo[2,3-b]pyridine series (7-azaindoles), was selected for further optimization in part on the basis of binding affinity (Ki) as well as on the basis of cellular potency. Optimization of this chemical series led to the identification of VX-509 (decernotinib), a novel, potent, and selective JAK3 inhibitor, which demonstrates good efficacy in vivo in the rat host versus graft model (HvG). On the basis of these findings, it appears that VX-509 offers potential for the treatment of a variety of autoimmune diseases.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Compostos Heterocíclicos com 2 Anéis/química , Janus Quinase 3/antagonistas & inibidores , Valina/análogos & derivados , Animais , Linhagem Celular , Bases de Dados de Compostos Químicos , Cães , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/imunologia , Haplorrinos , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Compostos Heterocíclicos com 2 Anéis/farmacologia , Humanos , Janus Quinase 2/química , Janus Quinase 3/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos CBA , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Valina/química , Valina/farmacocinética , Valina/farmacologia
4.
J Org Chem ; 64(1): 242-251, 1999 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-11674109

RESUMO

Syntheses of the potent sulfur-containing tetrapeptide mimetic farnesyl transferase inhibitors B956 (22) and B957 (23) are described. The two double bonds in 22 and 23 were constructed by application of iterative NHK and cuprate S(N)2' reactions. Normal syn NHK reaction and substrate-dependent syn and anti-S(N)2' diastereoselectivities accompanied by exclusive E-olefin selectivity were observed for the first NHK iteration (1 --> 4). In the second iteration, unexpected epimerization and a strong preference for syn diastereoselectivity was observed for the NHK reaction (5b --> 7a + 9a) while an unusual Z-olefin was observed for the S(N)2' reaction (7b --> 11). Deprotection conditions were optimized to ensure high purity and yield of the final aminothiol compounds.

5.
ACS Med Chem Lett ; 2(10): 758-63, 2011 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-24900264

RESUMO

The synthesis of novel, selective, orally active 2,5-disubstituted 6H-pyrimido[1,6-b]pyridazin-6-one p38α inhibitors is described. Application of structural information from enzyme-ligand complexes guided the selection of screening compounds, leading to the identification of a novel class of p38α inhibitors containing a previously unreported bicyclic heterocycle core. Advancing the SAR of this series led to the eventual discovery of 5-(2,6-dichlorophenyl)-2-(2,4-difluorophenylthio)-6H-pyrimido[1,6-b]pyridazin-6-one (VX-745). VX-745 displays excellent enzyme activity and selectivity, has a favorable pharmacokinetic profile, and demonstrates good in vivo activity in models of inflammation.

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