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1.
Nat Chem Biol ; 15(8): 846, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31267096

RESUMO

In the version of this article originally published, several lines of text in the last paragraph of the right column on page 1 of the PDF were transposed into the bottom paragraph of the left column. The affected text of the left column should read "The ATP-dependent activities of the BAF (SWI/SNF) chromatin remodeling complexes affect the positioning of nucleosomes on DNA and thereby many cellular processes related to chromatin structure, including transcription, DNA repair and decatenation of chromosomes during mitosis12,13." The affected text of the right column should read "SMARCA2/4BD inhibitors are thus precluded from use for the treatment of SMARCA4 mutant cancers but could provide attractive ligands for PROTAC conjugation. Small molecules binding to other bromodomains have been successfully converted into PROTACs by conjugating them with structures capable of binding to the E3 ligases von Hippel-Lindau (VHL) or cereblon5,6,10,11,25,26,27." The errors have been corrected in the PDF version of the paper.

2.
Nat Chem Biol ; 15(7): 672-680, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31178587

RESUMO

Targeting subunits of BAF/PBAF chromatin remodeling complexes has been proposed as an approach to exploit cancer vulnerabilities. Here, we develop proteolysis targeting chimera (PROTAC) degraders of the BAF ATPase subunits SMARCA2 and SMARCA4 using a bromodomain ligand and recruitment of the E3 ubiquitin ligase VHL. High-resolution ternary complex crystal structures and biophysical investigation guided rational and efficient optimization toward ACBI1, a potent and cooperative degrader of SMARCA2, SMARCA4 and PBRM1. ACBI1 induced anti-proliferative effects and cell death caused by SMARCA2 depletion in SMARCA4 mutant cancer cells, and in acute myeloid leukemia cells dependent on SMARCA4 ATPase activity. These findings exemplify a successful biophysics- and structure-based PROTAC design approach to degrade high profile drug targets, and pave the way toward new therapeutics for the treatment of tumors sensitive to the loss of BAF complex ATPases.


Assuntos
Montagem e Desmontagem da Cromatina/genética , Proteínas de Ligação a DNA/genética , Leucemia Mieloide Aguda/genética , Proteínas Nucleares/genética , Proliferação de Células , Células Cultivadas , Proteínas de Ligação a DNA/metabolismo , Humanos , Leucemia Mieloide Aguda/metabolismo , Estrutura Molecular , Proteínas Nucleares/metabolismo
3.
J Med Chem ; 62(5): 2508-2520, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30739444

RESUMO

Focal adhesion tyrosine kinase (PTK2) is often overexpressed in human hepatocellular carcinoma (HCC), and several reports have linked PTK2 depletion and/or pharmacological inhibition to reduced tumorigenicity. However, the clinical relevance of targeting PTK2 still remains to be proven. Here, we present two highly selective and functional PTK2 proteolysis-targeting chimeras utilizing von Hippel-Lindau and cereblon ligands to hijack E3 ligases for PTK2 degradation. BI-3663 (cereblon-based) degrades PTK2 with a median DC50 of 30 nM to >80% across a panel of 11 HCC cell lines. Despite effective PTK2 degradation, these compounds did not phenocopy the reported antiproliferative effects of PTK2 depletion in any of the cell lines tested. By disclosing these compounds, we hope to provide valuable tools for the study of PTK2 degradation across different biological systems.

4.
ChemMedChem ; 10(4): 727-35, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25759009

RESUMO

With the goal of identifying inhibitors of hepatitis C virus (HCV) NS3/4a protease that are potent against a wide range of genotypes and clinically relevant mutant viruses, several subseries of macrocycles were investigated based on observations made during the discovery of MK-5172. Quinazolinone-containing macrocycles were identified as promising leads, and optimization for superior cross-genotype and mutant enzyme potency as well as rat liver and plasma concentrations following oral dosing, led to the development of MK-2748. Additional investigation of a series of bis-macrocycles containing a fused 18- and 15-membered ring system were also optimized for the same properties, leading to the discovery of MK-6325. Both compounds display the broad genotype and mutant potency necessary for clinical development as next-generation HCV NS3/4a protease inhibitors.


Assuntos
Antivirais/farmacologia , Hepacivirus/enzimologia , Compostos Macrocíclicos/farmacologia , Quinazolinonas/farmacologia , Sulfonas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/química , Antivirais/farmacocinética , Cristalografia por Raios X , Descoberta de Drogas , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacocinética , Modelos Moleculares , Mutação , Quinazolinonas/química , Quinazolinonas/farmacocinética , Ratos , Sulfonas/farmacocinética , Proteínas não Estruturais Virais/genética
5.
Front Immunol ; 3: 334, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23162552

RESUMO

Dengue viruses (DENV) are the most important mosquito transmitted viral pathogens infecting humans. DENV infection produces a spectrum of disease, most commonly causing a self-limiting flu-like illness known as dengue fever; yet with increased frequency, manifesting as life-threatening dengue hemorrhagic fever (DHF). Waning cross-protective immunity from any of the four dengue serotypes may enhance subsequent infection with another heterologous serotype to increase the probability of DHF. Decades of effort to develop dengue vaccines are reaching the finishing line with multiple candidates in clinical trials. Nevertheless, concerns remain that imbalanced immunity, due to the prolonged prime-boost schedules currently used in clinical trials, could leave some vaccinees temporarily unprotected or with increased susceptibility to enhanced disease. Here we develop a DENV serotype 1 (DENV-1) DNA vaccine with the immunodominant cross-reactive B cell epitopes associated with immune enhancement removed. We compare wild-type (WT) with this cross-reactivity reduced (CRR) vaccine and demonstrate that both vaccines are equally protective against lethal homologous DENV-1 challenge. Under conditions mimicking natural exposure prior to acquiring protective immunity, WT vaccinated mice enhanced a normally sub-lethal heterologous DENV-2 infection resulting in DHF-like disease and 95% mortality in AG129 mice. However, CRR vaccinated mice exhibited redirected serotype-specific and protective immunity, and significantly reduced morbidity and mortality not differing from naїve mice. Thus, we demonstrate in an in vivo DENV disease model, that non-protective vaccine-induced immunity can prime vaccinees for enhanced DHF-like disease and that CRR DNA immunization significantly reduces this potential vaccine safety concern. The sculpting of immune memory by the modified vaccine and resulting redirection of humoral immunity provide insight into DENV vaccine-induced immune responses.

6.
Bioorg Med Chem Lett ; 22(23): 7207-13, 2012 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-23084906

RESUMO

A series of macrocyclic compounds containing a cyclic constraint in the P2-P4 linker region have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K, A156T, A156V, and D168V mutant activity while maintaining high rat liver exposure. The effect of the constraint is most dramatic against gt 1b A156 mutants where ~20-fold improvements in potency are achieved by introduction of a variety of ring systems into the P2-P4 linker.


Assuntos
Proteínas de Transporte/antagonistas & inibidores , Hepacivirus/enzimologia , Compostos Macrocíclicos/química , Inibidores de Proteases/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Sítios de Ligação , Proteínas de Transporte/metabolismo , Domínio Catalítico , Ciclização , Genótipo , Meia-Vida , Hepacivirus/genética , Cinética , Fígado/metabolismo , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacocinética , Simulação de Acoplamento Molecular , Mutação , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Ratos , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismo
7.
Bioorg Med Chem Lett ; 22(23): 7201-6, 2012 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-23021993

RESUMO

A series of macrocyclic compounds containing 2-substituted-quinoline moieties have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K mutant activity while maintaining the high rat liver exposure. Cyclization of the 2-substituted quinoline substituent led to a series of tricyclic P2 compounds which also display superb gt3a potency.


Assuntos
Proteínas de Transporte/antagonistas & inibidores , Hepacivirus/enzimologia , Compostos Macrocíclicos/química , Inibidores de Proteases/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Proteínas de Transporte/metabolismo , Ciclização , Genótipo , Meia-Vida , Hepacivirus/genética , Cinética , Fígado/metabolismo , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacocinética , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Quinolinas/química , Ratos , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismo
8.
ACS Med Chem Lett ; 3(4): 332-6, 2012 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-24900473

RESUMO

A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 15 (MK-5172), which is active against genotype 1-3 NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.

9.
ACS Chem Neurosci ; 2(7): 352-62, 2011 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-22816022

RESUMO

A series of 3-substituted aminocyclopentanes has been identified as highly potent and selective NR2B receptor antagonists. Incorporation of a 1,2,4-oxadiazole linker and substitution of the pendant phenyl ring led to the discovery of orally bioavailable analogues that showed efficient NR2B receptor occupancy in rats. Unlike nonselective NMDA antagonists, the NR2B-selective antagonist 22 showed no adverse affects on motor coordination in the rotarod assay at high dose. Compound 22 was efficacious following oral administration in a spinal nerve ligation model of neuropathic pain and in an acute model of Parkinson's disease in a dose dependent manner.


Assuntos
Ciclopentanos/síntese química , Ciclopentanos/farmacologia , Descoberta de Drogas/métodos , Antagonistas de Aminoácidos Excitatórios/síntese química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Administração Oral , Animais , Benzopiranos/metabolismo , Disponibilidade Biológica , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Cães , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Feminino , Meia-Vida , Indicadores e Reagentes , Isomerismo , Ligadura , Macaca mulatta , Masculino , Neuralgia/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Piperidinas/metabolismo , Ratos , Ratos Sprague-Dawley , Nervos Espinhais/patologia
10.
ACS Med Chem Lett ; 2(3): 207-12, 2011 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-24900304

RESUMO

The discovery of MK-1220 is reported along with the development of a series of HCV NS3/4A protease inhibitors containing a P2 to P4 macrocyclic constraint with improved preclinical pharmacokinetics. Optimization of the P2 heterocycle substitution pattern as well as the P3 amino acid led to compounds with greatly improved plasma exposure following oral dosing in both rats and dogs while maintaining excellent enzyme potency and cellular activity. These studies led to the identification of MK-1220.

11.
J Med Chem ; 53(6): 2443-63, 2010 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-20163176

RESUMO

A new class of HCV NS3/4a protease inhibitors which contain a P2 to P4 macrocyclic constraint was designed using a molecular-modeling derived strategy. Exploration of the P2 heterocyclic region, the P2 to P4 linker, and the P1 side chain of this class of compounds via a modular synthetic strategy allowed for the optimization of enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 35b (vaniprevir, MK-7009), which is active against both the genotype 1 and genotype 2 NS3/4a protease enzymes and has good plasma exposure and excellent liver exposure in multiple species.


Assuntos
Hepacivirus/enzimologia , Indóis/farmacologia , Inibidores de Serino Proteinase/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Área Sob a Curva , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/metabolismo , Cães , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Indóis/química , Indóis/farmacocinética , Concentração Inibidora 50 , Fígado/metabolismo , Macaca mulatta , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacocinética , Compostos Macrocíclicos/farmacologia , Taxa de Depuração Metabólica , Modelos Químicos , Estrutura Molecular , Pan troglodytes , Ratos , Inibidores de Serino Proteinase/química , Inibidores de Serino Proteinase/farmacocinética , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismo , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/metabolismo
12.
J Gen Virol ; 88(Pt 4): 1169-74, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17374760

RESUMO

Human flavivirus infections elicit virus species-specific and cross-reactive immune responses. The flavivirus envelope (E) glycoprotein is the primary antigen inducing protective immunity; however, the presence of cross-reactive antibodies in human sera creates problems for serodiagnosis. Using a West Nile virus-like particle system, we performed mutagenesis across all three E protein functional domains to identify epitope determinants for a panel of monoclonal antibodies (mAbs) raised against different flaviviruses and exhibiting diverse patterns of cross-reactivity. Residues within the highly conserved fusion peptide were the only epitope determinants identified and were important not only for broadly cross-reactive mAbs recognizing all of the medically important flavivirus serocomplexes, but also for less-broad, complex-reactive mAbs. Moreover, different substitutions at specific fusion peptide residues produced highly variable effects on antibody reactivity and virus-like particle secretion. These results support and extend the conclusion that the fusion peptide region constitutes an immunodominant epitope stimulating antibodies with diverse patterns of cross-reactivity.


Assuntos
Antígenos Virais/imunologia , Epitopos/imunologia , Proteínas do Envelope Viral/imunologia , Vírus do Nilo Ocidental/imunologia , Substituição de Aminoácidos , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , Antígenos Virais/genética , Células CHO , Cricetinae , Cricetulus , Reações Cruzadas , Epitopos/genética , Epitopos Imunodominantes/genética , Epitopos Imunodominantes/imunologia , Mutagênese Sítio-Dirigida , Proteínas do Envelope Viral/genética , Vírus do Nilo Ocidental/genética
13.
Virology ; 360(2): 398-406, 2007 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-17157348

RESUMO

The immune response to flavivirus infections produces both species-specific and flavivirus cross-reactive antibodies. The presence of cross-reactive antibodies complicates serodiagnosis of flavivirus infections, especially secondary infections caused by a heterologous virus. A successful public health response to the growing global threat posed by flaviviruses necessitates the development of virus-specific diagnostic antigens. The flavivirus envelope (E) glycoprotein is the principle antigen stimulating protective immunity during infection. Using recombinant St. Louis encephalitis virus-like particles (VLPs), we have identified amino acid residues involved in flavivirus cross-reactive epitope determinants. Most significant among the residues studied are three highly conserved amino acids in the fusion peptide: Gly104, Gly106, and Leu107. Substitutions of these residues dramatically influenced VLP secretion and cross-reactive monoclonal antibody reactivity. These results provide critical insight into the antigenic structure of the flaviviral E protein and toward development of species-specific diagnostic antigens that should improve both flavivirus diagnosis and estimates of disease burden.


Assuntos
Vírus da Encefalite de St. Louis/imunologia , Epitopos/genética , Epitopos/imunologia , Mutação , Proteínas do Envelope Viral/imunologia , Proteínas Virais de Fusão/imunologia , Substituição de Aminoácidos , Anticorpos Monoclonais/imunologia , Vírus da Encefalite de St. Louis/genética , Mutagênese Sítio-Dirigida , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteínas do Envelope Viral/genética , Proteínas Virais de Fusão/genética
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