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1.
J Med Chem ; 64(9): 5787-5801, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33872011

RESUMO

The use of epigenetic bromodomain inhibitors as anticancer therapeutics has transitioned from targeting bromodomain extraterminal domain (BET) proteins into targeting non-BET bromodomains. The two most relevant non-BET bromodomain oncology targets are cyclic AMP response element-binding protein (CBP) and E1A binding protein P300 (EP300). To explore the growing CBP/EP300 interest, we developed a highly efficient two-step synthetic route for dimethylisoxazole-attached imidazo[1,2-a]pyridine scaffold-containing inhibitors. Our efficient two-step reactions enabled high-throughput synthesis of compounds designed by molecular modeling, which together with structure-activity relationship (SAR) studies facilitated an overarching understanding of selective targeting of CBP/EP300 over non-BET bromodomains. This led to the identification of a new potent and selective CBP/EP300 bromodomain inhibitor, UMB298 (compound 23, CBP IC50 72 nM and bromodomain 4, BRD4 IC50 5193 nM). The SAR we established is in good agreement with literature-reported CBP inhibitors, such as CBP30, and demonstrates the advantage of utilizing our two-step approach for inhibitor development of other bromodomains.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/antagonistas & inibidores , Proteína p300 Associada a E1A/antagonistas & inibidores , Isoxazóis/química , Piridinas/química , Sítios de Ligação , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteína p300 Associada a E1A/metabolismo , Humanos , Simulação de Acoplamento Molecular , Piridinas/metabolismo , Piridinas/farmacologia , Relação Estrutura-Atividade , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo
2.
Arch Microbiol ; 203(2): 629-634, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33006037

RESUMO

This investigation assessed the synergistic effectiveness of alkyltrimethylammonium bromide (ATMB) and chlorhexidine digluconate (CDG) on selected microbes causing red-heat and purple stain degradations on salt-cured hides and leather products. This biological phenomenon ultimately deteriorates the finished leather quality and grounds considerable economic losses for leather industry. In tryptic soy broth, combination of ATMB and/CDG at the concentration of 900/90 ppm for predefined time interval of 1, 3, and 6 min caused in 0.73, 2.45, and 2.95 log CFU/mL reductions of bacterial cocktail population cell survival, respectively. Whereas in saturated brine solution (SBS), the bacterial cocktail treated with 600/60 and 900/90 ppm of ATMB/CDG for 18 h resulted ~ 74% and 98% reduction, respectively, in comparison to their respective controls. Furthermore, lessening of individual bacterial cultivations by combined ATMB and CDG in SBS was also elucidated.


Assuntos
Bactérias/efeitos dos fármacos , Brometos/farmacologia , Clorexidina/análogos & derivados , Microbiologia Industrial , Clorexidina/farmacologia , Sais , Cloreto de Sódio
3.
Sci Adv ; 6(29): eaba1941, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32832623

RESUMO

Although combination antiretroviral therapy is effective in controlling HIV-1 infection, latent HIV-1 proviruses cannot be eliminated. HIV-1 reactivation induced by the mere use of latency-reversing agents is insufficient to render death of reservoir cells, indicating that certain intrinsic survival mechanisms exist. We report that Polo-like kinase 1 (PLK1) plays a critical role in survival of CD4+ T cells that undergo HIV-1 reactivation from latency or de novo infection. PLK1 is elevated in both scenarios, which requires HIV-1 Nef. HIV-1 enhances PLK1 SUMOylation, causing its nuclear translocation and protein stabilization. Inhibition or knockdown of PLK1 markedly facilitates death of HIV-1-infected CD4+ T cells. Furthermore, PLK1 inhibitors strikingly reduce the size of HIV-1 latent reservoirs in primary CD4+ T cells. Our findings demonstrate that HIV-1 infection hijacks PLK1 to prevent cell death induced by viral cytopathic effects, and that PLK1 is a promising target for chemical "killing" of HIV-1 reservoir cells.


Assuntos
Linfócitos T CD4-Positivos , Proteínas de Ciclo Celular , Infecções por HIV , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , HIV-1/fisiologia , Humanos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Ativação Viral , Latência Viral , Quinase 1 Polo-Like
4.
Transl Oncol ; 13(2): 221-232, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31869746

RESUMO

Simultaneous inhibition of multiple molecular targets is an established strategy to improve the continuance of clinical response to therapy. Here, we screened 49 molecules with dual nanomolar inhibitory activity against BRD4 and PLK1, best classified as dual kinase-bromodomain inhibitors, in pediatric tumor cell lines for their antitumor activity. We identified two candidate dual kinase-bromodomain inhibitors with strong and tumor-specific activity against neuroblastoma, medulloblastoma, and rhabdomyosarcoma tumor cells. Dual PLK1 and BRD4 inhibitor treatment suppressed proliferation and induced apoptosis in pediatric tumor cell lines at low nanomolar concentrations. This was associated with reduced MYCN-driven gene expression as assessed by RNA sequencing. Treatment of patient-derived xenografts with dual inhibitor UMB103 led to significant tumor regression. We demonstrate that concurrent inhibition of two central regulators of MYC protein family of protooncogenes, BRD4, and PLK1, with single small molecules has strong and specific antitumor effects in preclinical pediatric cancer models.

5.
J Med Chem ; 61(17): 7785-7795, 2018 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-30125504

RESUMO

The simultaneous inhibition of polo-like kinase 1 (PLK1) and BRD4 bromodomain by a single molecule could lead to the development of an effective therapeutic strategy for a variety of diseases in which PLK1 and BRD4 are implicated. Compound 23 has been found to be a potent dual kinase-bromodomain inhibitor (BRD4-BD1 IC50 = 28 nM, PLK1 IC50 = 40 nM). Compound 6 was found to be the most selective PLK1 inhibitor over BRD4 in our series (BRD4-BD1 IC50 = 2579 nM, PLK1 IC50 = 9.9 nM). Molecular docking studies with 23 and BRD4-BD1/PLK1 as well as with 6 corroborate the biochemical assay results.


Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Desenho de Fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas Nucleares/antagonistas & inibidores , Conformação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Humanos , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/patologia , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Domínios Proteicos , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Quinase 1 Polo-Like
6.
Front Microbiol ; 8: 1035, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28638377

RESUMO

While combinatory antiretroviral therapy (cART) can effectively reduce HIV-1 viremia, it cannot eliminate HIV-1 infection. In the presence of cART, viral reservoirs remain latent, impeding the cure of HIV-1/AIDS. Recently, latency-reversing agents (LRAs) have been developed with the intent of purging latent HIV-1, providing an intriguing strategy for the eradication of the residual viral reservoirs. Our earlier studies show that the first-generation, methyl-triazolo bromodomain, and extra-terminal domain inhibitor (BETi), JQ1, facilitates the reversal of HIV-1 latency. BETis have emerged as a new class of compounds that are promising for this HIV-1 "shock and kill" eradication approach. However, when used as a single drug, JQ1 only modestly reverses HIV-1 latency, which complicates studying the underlining mechanisms. Meanwhile, it has been widely discussed that the induction of latent proviruses is stochastic (Ho et al., 2013). Thus, new BETis are currently under active development with focus on improving potency, ease of synthesis and structural diversity. Using fluorous-tagged multicomponent reactions, we developed a novel second-generation, 3,5-dimethylisoxazole BETi based on an imidazo[1,2-a] pyrazine scaffold, UMB-32. Furthermore, we screened 37 UMB-32 derivatives and identified that one, UMB-136, reactivates HIV-1 in multiple cell models of HIV-1 latency with better efficiency than either JQ1 or UMB-32. UMB-136 enhances HIV-1 transcription and increases viral production through the release of P-TEFb. Importantly, UMB-136 enhances the latency-reversing effects of PKC agonists (prostratin, bryostatin-1) in CD8-depleted PBMCs containing latent viral reservoirs. Our results illustrate that structurally improved BETis, such as UMB-136, may be useful as promising LRAs for HIV-1 eradication.

7.
Infect Immun ; 81(8): 2753-60, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23690406

RESUMO

The two major forms of Shiga toxin, Stx1 and Stx2, use the glycolipid globotriaosylceramide (Gb3) as their cellular receptor. Stx1 primarily recognizes the Pk-trisaccharide portion and has three Pk binding sites per B monomer. The Stx2a subtype requires glycolipid residues in addition to Pk. We synthesized analogs of Pk to examine the binding preferences of Stx1 and Stx2 subtypes a to d. Furthermore, to determine how many binding sites must be engaged, the Pk analogues were conjugated to biotinylated mono- and biantennary platforms, allowing for the display of two to four Pk analogues per streptavidin molecule. Stx binding to Pk analogues immobilized on streptavidin-coated plates was assessed by enzyme-linked immunosorbent assay (ELISA). Stx1, but not the Stx2 subtypes, bound to native Pk. Stx2a and Stx2c bound to the Pk analog with a terminal GalNAc (NAc-Pk), while Stx1, Stx2b, and Stx2d did not bind to this analog. Interestingly, the purified Stx2d B subunit bound to NAc-Pk, suggesting that the A subunit of Stx2d interferes with binding. Disaccharide analogs (Galα1-4Gal, GalNAcα1-4Gal, and Galα1-4GalNAc) did not support the binding of any of the Stx forms, indicating that the trisaccharide is necessary for binding. Studies with monoantennary and biantennary analogs and mixtures suggest that Stx1, Stx2a, and Stx2c need to engage at least three Pk analogues for effective binding. To our knowledge, this is the first study examining the minimum number of Pk analogs required for effective binding and the first report documenting the role of the A subunit in influencing Stx2 binding.


Assuntos
Toxinas Shiga/química , Triexosilceramidas/química , Trissacarídeos/química , Sequência de Aminoácidos , Western Blotting , Eletroforese em Gel de Poliacrilamida , Ensaio de Imunoadsorção Enzimática , Dados de Sequência Molecular , Ligação Proteica , Toxinas Shiga/metabolismo , Trissacarídeos/metabolismo
8.
Chembiochem ; 14(2): 251-9, 2013 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-23307594

RESUMO

Biotinylated mono- and biantennary di-/trisaccharides were synthesized to evaluate their ability to capture E. coli strains that express pilus types with different receptor specificities. The synthesized biotinylated di-/trisaccharides contain Galα(1→4)Gal, Galα(1→4)GalNHAc, GalNHAcα(1→4)Gal, Galα(1→4)Galß(1→4)Glc and GalNHAcα(1→4)Galß(1→4)Glc as carbohydrate epitopes. These biotinylated oligosaccharides were immobilized on streptavidin-coated magnetic beads, and incubated with different strains of live E. coli. Capturing ability was assessed by using a luciferase assay that detects bacterial ATP. The trisaccharides containing Galα(1→4)Galß(1→4)Glc and the disaccharides containing Galα(1→4)Gal as the epitopes exhibited strong capturing ability for uropathogenic E. coli strains with the pap pilus genotype, including CFT073, J96 and J96 pilE. The same ligands failed to capture E. coli strains with fim, prs, or foc genotypes. Uropathogenic CFT073 was also captured moderately by biantennary disaccharides containing a GalNHAc moiety at the reducing end; however, other saccharides containing GalNHAc at the nonreducing end did not capture the CFT073 strain. These synthetic glycoconjugates could potentially be adapted as rapid diagnostic agents to differentiate between different E. coli pathovars.


Assuntos
Dissacarídeos/metabolismo , Infecções por Escherichia coli/diagnóstico , Escherichia coli/isolamento & purificação , Glicoconjugados/metabolismo , Trissacarídeos/metabolismo , Sítios de Ligação , Biotinilação , Sequência de Carboidratos , Dissacarídeos/química , Escherichia coli/metabolismo , Infecções por Escherichia coli/microbiologia , Glicoconjugados/química , Humanos , Ligantes , Dados de Sequência Molecular , Trissacarídeos/química
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