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1.
Mol Cancer Ther ; 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31439712

RESUMO

KRAS, an oncogene mutated in nearly one-third of human cancers, remains a pharmacological challenge for direct inhibition except for recent advances in selective inhibitors targeting the G12C variant. Here, we report that selective inhibition of the protein tyrosine phosphatase, SHP2, can impair the proliferation of KRAS mutant cancer cells in vitro and in vivo using cell line xenografts and primary human tumors. In vitro, sensitivity of KRAS mutant cells towards the allosteric SHP2 inhibitor, SHP099, is not apparent when cells are gown on plastic in 2D monolayer, but is revealed when cells are grown as 3D multicellular spheroids. This anti-tumor activity is also observed in vivo in mouse models. Interrogation of the MAPK pathway in SHP099 treated KRAS-mutant cancer models demonstrated similar modulation of p-ERK and DUSP6 transcripts in 2D, 3D and in vivo, suggesting a MAPK pathway dependent mechanism and possible non-MAPK pathway dependent mechanisms in tumor cells or tumor microenvironment for the in vivo efficacy. For the KRASG12C MIAPaCa-2 model, we demonstrate that the efficacy is cancer cell intrinsic as there is minimal anti-angiogenic activity by SHP099, and the effects of SHP099 is recapitulated by genetic depletion of SHP2 in cancer cells. Furthermore, we demonstrate that SHP099 efficacy in KRAS mutant models can be recapitulated with RTK inhibitors, suggesting RTK activity is responsible for the SHP2 activation. Taken together, these data reveal that many KRAS-mutant cancers depend on upstream signaling from RTK and SHP2, and provide a new therapeutic framework for treating KRAS mutant cancers with SHP2 inhibitors.

4.
J Med Chem ; 62(4): 1793-1802, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30688459

RESUMO

Protein tyrosine phosphatase SHP2 is an oncoprotein associated with cancer as well as a potential immune modulator because of its role in the programmed cell death PD-L1/PD-1 pathway. In the preceding manuscript, we described the optimization of a fused, bicyclic screening hit for potency, selectivity, and physicochemical properties in order to further expand the chemical diversity of allosteric SHP2 inhibitors. In this manuscript, we describe the further expansion of our approach, morphing the fused, bicyclic system into a novel monocyclic pyrimidinone scaffold through our understanding of SAR and use of structure-based design. These studies led to the identification of SHP394 (1), an orally efficacious inhibitor of SHP2, with high lipophilic efficiency, improved potency, and enhanced pharmacokinetic properties. We also report other pyrimidinone analogues with favorable pharmacokinetic and potency profiles. Overall, this work improves upon our previously described allosteric inhibitors and exemplifies and extends the range of permissible chemical templates that inhibit SHP2 via the allosteric mechanism.

5.
J Med Chem ; 62(4): 1781-1792, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30688462

RESUMO

SHP2 is a nonreceptor protein tyrosine phosphatase within the mitogen-activated protein kinase (MAPK) pathway controlling cell growth, differentiation, and oncogenic transformation. SHP2 also participates in the programed cell death pathway (PD-1/PD-L1) governing immune surveillance. Small-molecule inhibition of SHP2 has been widely investigated, including in our previous reports describing SHP099 (2), which binds to a tunnel-like allosteric binding site. To broaden our approach to allosteric inhibition of SHP2, we conducted additional hit finding, evaluation, and structure-based scaffold morphing. These studies, reported here in the first of two papers, led to the identification of multiple 5,6-fused bicyclic scaffolds that bind to the same allosteric tunnel as 2. We demonstrate the structural diversity permitted by the tunnel pharmacophore and culminated in the identification of pyrazolopyrimidinones (e.g., SHP389, 1) that modulate MAPK signaling in vivo. These studies also served as the basis for further scaffold morphing and optimization, detailed in the following manuscript.

6.
Nat Commun ; 9(1): 4508, 2018 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-30375388

RESUMO

Activating mutations in PTPN11, encoding the cytosolic protein tyrosine phosphatase SHP2, result in developmental disorders and act as oncogenic drivers in patients with hematologic cancers. The allosteric inhibitor SHP099 stabilizes the wild-type SHP2 enzyme in an autoinhibited conformation that is itself destabilized by oncogenic mutations. Here, we report the impact of the highly activated and most frequently observed mutation, E76K, on the structure of SHP2, and investigate the effect of E76K and other oncogenic mutations on allosteric inhibition by SHP099. SHP2E76K adopts an open conformation but can be restored to the closed, autoinhibited conformation, near-identical to the unoccupied wild-type enzyme, when complexed with SHP099. SHP099 inhibitory activity against oncogenic SHP2 variants in vitro and in cells scales inversely with the activating strength of the mutation, indicating that either oncoselective or vastly more potent inhibitors will be necessary to suppress oncogenic signaling by the most strongly activating SHP2 mutations in cancer.

7.
ACS Chem Biol ; 13(3): 647-656, 2018 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-29304282

RESUMO

SHP2 is a cytoplasmic protein tyrosine phosphatase encoded by the PTPN11 gene and is involved in cell proliferation, differentiation, and survival. Recently, we reported an allosteric mechanism of inhibition that stabilizes the auto-inhibited conformation of SHP2. SHP099 (1) was identified and characterized as a moderately potent, orally bioavailable, allosteric small molecule inhibitor, which binds to a tunnel-like pocket formed by the confluence of three domains of SHP2. In this report, we describe further screening strategies that enabled the identification of a second, distinct small molecule allosteric site. SHP244 (2) was identified as a weak inhibitor of SHP2 with modest thermal stabilization of the enzyme. X-ray crystallography revealed that 2 binds and stabilizes the inactive, closed conformation of SHP2, at a distinct, previously unexplored binding site-a cleft formed at the interface of the N-terminal SH2 and PTP domains. Derivatization of 2 using structure-based design resulted in an increase in SHP2 thermal stabilization, biochemical inhibition, and subsequent MAPK pathway modulation. Downregulation of DUSP6 mRNA, a downstream MAPK pathway marker, was observed in KYSE-520 cancer cells. Remarkably, simultaneous occupation of both allosteric sites by 1 and 2 was possible, as characterized by cooperative biochemical inhibition experiments and X-ray crystallography. Combining an allosteric site 1 inhibitor with an allosteric site 2 inhibitor led to enhanced pharmacological pathway inhibition in cells. This work illustrates a rare example of dual allosteric targeted protein inhibition, demonstrates screening methodology and tactics to identify allosteric inhibitors, and enables further interrogation of SHP2 in cancer and related pathologies.

8.
Bioorg Med Chem ; 25(24): 6479-6485, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29089257

RESUMO

The PTPN11 oncogene encodes the cytoplasmic protein tyrosine phosphatase SHP2, which, through its role in multiple signaling pathways, promotes the progression of hematological malignancies and other cancers. Here, we employ high-throughput screening to discover a lead chemical scaffold, the benzothiazolopyrimidones, that allosterically inhibits this oncogenic phosphatase by simultaneously engaging the C-SH2 and PTP domains. We improved our lead to generate an analogue that better suppresses SHP2 activity in vitro. Suppression of Erk phopsphorylation by the lead compound is also consistent with SHP2 inhibition in AML cells. Our findings provide an alternative starting point for therapeutic intervention and will catalyze investigations into the relationship between SHP2 conformational regulation, activity, and disease progression.


Assuntos
Benzotiazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Pirimidinonas/farmacologia , Regulação Alostérica/efeitos dos fármacos , Benzotiazóis/síntese química , Benzotiazóis/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Pirimidinonas/síntese química , Pirimidinonas/química , Relação Estrutura-Atividade
9.
Nature ; 535(7610): 148-52, 2016 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-27362227

RESUMO

The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported oncogenic tyrosine phosphatase. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS­ERK signalling pathway. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy. Here we report the discovery of a highly potent (IC50 = 0.071 µM), selective and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an auto-inhibited conformation. SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppresses RAS­ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models. Together, these data demonstrate that pharmacological inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers.


Assuntos
Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Piperidinas/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Pirimidinas/farmacologia , Receptores Proteína Tirosina Quinases/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Concentração Inibidora 50 , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Nus , Modelos Moleculares , Neoplasias/patologia , Proteína Oncogênica p21(ras)/metabolismo , Piperidinas/química , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Estabilidade Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína/efeitos dos fármacos , Proteína Tirosina Fosfatase não Receptora Tipo 11/química , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Pirimidinas/química , Pirimidinas/uso terapêutico , Reprodutibilidade dos Testes , Ensaios Antitumorais Modelo de Xenoenxerto
10.
J Med Chem ; 59(14): 6920-8, 2016 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-27355833

RESUMO

Synthetic studies of the antimicrobial secondary metabolite thiomuracin A (1) provided access to analogues in the Northern region (C2-C10). Selective hydrolysis of the C10 amide of lead compound 2 and subsequent derivatization led to novel carbon- and nitrogen-linked analogues (e.g., 3) which improved antibacterial potency across a panel of Gram-positive organisms. In addition, congeners with improved physicochemical properties were identified which proved efficacious in murine sepsis and hamster C. difficile models of disease. Optimal efficacy in the hamster model of C. difficile was achieved with compounds that possessed both potent antibacterial activity and high aqueous solubility.


Assuntos
Antibacterianos/farmacologia , Infecções por Clostridium/tratamento farmacológico , Clostridium difficile/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Tiazóis/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Cricetinae , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Solubilidade , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
11.
J Med Chem ; 59(17): 7773-82, 2016 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-27347692

RESUMO

SHP2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also purportedly plays an important role in the programmed cell death pathway (PD-1/PD-L1). Because it is an oncoprotein associated with multiple cancer-related diseases, as well as a potential immunomodulator, controlling SHP2 activity is of significant therapeutic interest. Recently in our laboratories, a small molecule inhibitor of SHP2 was identified as an allosteric modulator that stabilizes the autoinhibited conformation of SHP2. A high throughput screen was performed to identify progressable chemical matter, and X-ray crystallography revealed the location of binding in a previously undisclosed allosteric binding pocket. Structure-based drug design was employed to optimize for SHP2 inhibition, and several new protein-ligand interactions were characterized. These studies culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099, 1), a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor.


Assuntos
Antineoplásicos/química , Piperidinas/química , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Pirazinas/química , Pirimidinas/química , Administração Oral , Regulação Alostérica , Sítio Alostérico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Desenho de Drogas , Feminino , Xenoenxertos , Ensaios de Triagem em Larga Escala , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Nus , Modelos Moleculares , Transplante de Neoplasias , Piperidinas/síntese química , Piperidinas/farmacocinética , Piperidinas/farmacologia , Conformação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 11/química , Pirazinas/síntese química , Pirazinas/farmacocinética , Pirazinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Relação Estrutura-Atividade
12.
Biochemistry ; 55(15): 2269-77, 2016 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-27030275

RESUMO

The proto-oncogene PTPN11 encodes a cytoplasmic protein tyrosine phosphatase, SHP2, which is required for normal development and sustained activation of the Ras-MAPK signaling pathway. Germline mutations in SHP2 cause developmental disorders, and somatic mutations have been identified in childhood and adult cancers and drive leukemia in mice. Despite our knowledge of the PTPN11 variations associated with pathology, the structural and functional consequences of many disease-associated mutants remain poorly understood. Here, we combine X-ray crystallography, small-angle X-ray scattering, and biochemistry to elucidate structural and mechanistic features of three cancer-associated SHP2 variants harboring single point mutations within the N-SH2:PTP interdomain autoinhibitory interface. Our findings directly compare the impact of each mutation on autoinhibition of the phosphatase and advance the development of structure-guided and mutation-specific SHP2 therapies.


Assuntos
Neoplasias/genética , Mutação Puntual , Proteína Tirosina Fosfatase não Receptora Tipo 11/química , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Substituição de Aminoácidos/genética , Transformação Celular Neoplásica/genética , Cristalografia por Raios X , Ativação Enzimática/genética , Humanos , Leucemia/genética , Ligantes , Modelos Moleculares , Oncogenes/genética , Estrutura Terciária de Proteína/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Espalhamento a Baixo Ângulo , Relação Estrutura-Atividade
13.
Bioorg Med Chem Lett ; 25(17): 3468-75, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26189081

RESUMO

We describe the synthesis and evaluation of a library of variably-linked ciprofloxacin dimers. These structures unify and expand on the use of fluoroquinolones as probes throughout the antibiotic literature. A dimeric analog (19) showed enhanced inhibition of its intracellular target (DNA gyrase), and translation to antibacterial activity in whole cells was demonstrated. Overall, cell permeation was governed by physicochemical properties and bacterial type. A principal component analysis demonstrated that the dimers occupy a unique and privileged region of chemical space most similar to the macrolide class of antibiotics.


Assuntos
Antibacterianos/síntese química , Anti-Infecciosos/síntese química , Ciprofloxacino/síntese química , DNA Bacteriano/metabolismo , Antibacterianos/química , Antibacterianos/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Ciprofloxacino/química , Ciprofloxacino/farmacologia , Permeabilidade
15.
J Med Chem ; 55(15): 6934-41, 2012 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-22812377

RESUMO

Synthetic studies of the antimicrobial secondary metabolite thiomuracin A (1) were initiated to improve chemical stability and physicochemical properties. Functional group modifications of 1 included removing the C2-C7 side chain, derivatizing the C84 epoxide region, and altering the C44 hydroxyphenylalanine motif. The resulting derivatives simplified and stabilized the chemical structure and were evaluated for antibacterial activity relative to 1. The simplified structure and improved organic solubility of the derivatives facilitated isolation yields from fermentation broths and simplified the procedures involved for the process. These advancements increased material supply for continued medicinal chemistry optimization and culminated in the identification of 2, a structurally simplified and chemically stable analogue of 1 which retained potent antibiotic activity.


Assuntos
Antibacterianos/síntese química , Peptídeos Cíclicos/síntese química , Tiazóis/síntese química , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Clostridium difficile/efeitos dos fármacos , Cristalografia por Raios X , Enterococcus/efeitos dos fármacos , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/biossíntese , Proteínas de Escherichia coli/química , Feminino , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Fator Tu de Elongação de Peptídeos/química , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Inibidores da Síntese de Proteínas/síntese química , Inibidores da Síntese de Proteínas/química , Inibidores da Síntese de Proteínas/farmacologia , Ratos , Ratos Sprague-Dawley , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pyogenes/efeitos dos fármacos , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologia , Transcrição Genética/efeitos dos fármacos
16.
J Med Chem ; 55(5): 2376-87, 2012 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-22315981

RESUMO

Clostridium difficile (C. difficile) is a Gram positive, anaerobic bacterium that infects the lumen of the large intestine and produces toxins. This results in a range of syndromes from mild diarrhea to severe toxic megacolon and death. Alarmingly, the prevalence and severity of C. difficile infection are increasing; thus, associated morbidity and mortality rates are rising. 4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for the treatment of C. difficile infection. The medicinal chemistry effort focused on enhancing aqueous solubility relative to that of the natural product and previous development candidates (2, 3) and improving antibacterial activity. Structure-activity relationships, cocrystallographic interactions, pharmacokinetics, and efficacy in animal models of infection were characterized. These studies identified a series of dicarboxylic acid derivatives, which enhanced solubility/efficacy profile by several orders of magnitude compared to previously studied compounds and led to the selection of LFF571 (4) as an investigational new drug for treating C. difficile infection.


Assuntos
Antibacterianos/síntese química , Clostridium difficile/efeitos dos fármacos , Enterocolite Pseudomembranosa/tratamento farmacológico , Tiazóis/síntese química , Animais , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Cricetinae , Cristalografia por Raios X , Enterococcus/efeitos dos fármacos , Proteínas de Escherichia coli/antagonistas & inibidores , Proteínas de Escherichia coli/química , Feminino , Masculino , Mesocricetus , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Fator Tu de Elongação de Peptídeos/antagonistas & inibidores , Fator Tu de Elongação de Peptídeos/química , Ratos , Ratos Sprague-Dawley , Solubilidade , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pyogenes/efeitos dos fármacos , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Água
17.
J Med Chem ; 54(23): 8099-109, 2011 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-21999529

RESUMO

4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for their activity against Gram positive bacterial infections. Optimization efforts focused on improving the physicochemical properties (e.g., aqueous solubility and chemical stability) of the 4-aminothiazolyl natural product template while improving the in vitro and in vivo antibacterial activity. Structure-activity relationships were defined, and the solubility and efficacy profiles were improved over those of previous analogues and 1. These studies identified novel, potent, soluble, and efficacious elongation factor-Tu inhibitors, which bear cycloalkylcarboxylic acid side chains, and culminated in the selection of development candidates amide 48 and urethane 58.


Assuntos
Antibacterianos/síntese química , Ácidos Carboxílicos/síntese química , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Peptídeos Cíclicos/síntese química , Tiazóis/síntese química , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Área Sob a Curva , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Cristalografia por Raios X , Farmacorresistência Bacteriana , Feminino , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/genética , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Mutação , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Ratos , Ratos Sprague-Dawley , Sepse/tratamento farmacológico , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologia
18.
Bioorg Med Chem Lett ; 21(11): 3210-5, 2011 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-21550238

RESUMO

Imidazole analogs of the antibiotic natural product GE2270 A (1) were designed, synthesized, and evaluated for gram positive bacteria growth inhibition. A recently reported, copper-mediated synthesis was exploited to prepare 4-thiazolyl imidazole analogs of 1. The synthesis described represents a structurally complex, natural product-based application of this recently reported synthetic methodology. In addition, the biological evaluation of the imidazole-based analogs further define the SAR of the 4-aminothiazolyl-based antibacterial template.


Assuntos
Aminas/síntese química , Antibacterianos , Bactérias Gram-Positivas/efeitos dos fármacos , Imidazóis/química , Peptídeos Cíclicos/química , Tiazóis/síntese química , Aminas/química , Aminas/farmacologia , Antibacterianos/síntese química , Antibacterianos/farmacologia , Cobre/química , Escherichia coli/efeitos dos fármacos , Imidazóis/síntese química , Imidazóis/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Peptídeos Cíclicos/farmacologia , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologia
19.
J Med Chem ; 54(7): 2517-21, 2011 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-21405087

RESUMO

4-Aminothiazolyl analogues of the antibacterial natural product GE2270 A (1) were designed, synthesized, and evaluated for gram positive bacteria growth inhibition. The aminothiazole-based chemical template was evaluated for chemical stability, and its decomposition revealed a novel, structurally simplified, des-thiazole analogue of 1. Subsequent stabilization of the 4-aminothiazolyl functional motif was achieved and initial structure activity relationships defined.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Descoberta de Drogas , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Tiazóis/química , Antibacterianos/síntese química , Bactérias/efeitos dos fármacos , Estabilidade de Medicamentos , Testes de Sensibilidade Microbiana , Peptídeos Cíclicos/síntese química , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacologia
20.
J Am Chem Soc ; 131(16): 5946-55, 2009 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-19338336

RESUMO

We identified the thiomuracins, a novel family of thiopeptides produced by a rare-actinomycete bacterium typed as a Nonomuraea species, via a screen for inhibition of growth of the bacterial pathogen Staphylococcus aureus. Thiopeptides are a class of macrocyclic, highly modified peptides that are decorated by thiazoles and defined by a central six-membered heterocyclic ring system. Mining the genomes of thiopeptide-producing strains revealed the elusive biosynthetic route for this class of antibiotics. The thiopeptides are chromosomally encoded, ribosomally synthesized proteins, and isolation of gene clusters for production of thiomuracin and the related thiopeptide GE2270A revealed the post-translational machinery required for maturation. The target of the thiomuracins was identified as bacterial Elongation Factor Tu (EF-Tu). In addition to potently inhibiting a target that is unexploited by marketed human therapeutics, the thiomuracins have a low propensity for selecting for antibiotic resistance and confer no measurable cross-resistance to antibiotics in clinical use.


Assuntos
Antibacterianos/farmacologia , Fator Tu de Elongação de Peptídeos/metabolismo , Peptídeos/genética , Peptídeos/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Tiazóis/farmacologia , Actinomycetales/química , Sequência de Aminoácidos , Antibacterianos/química , Antibacterianos/isolamento & purificação , Proteínas de Bactérias/isolamento & purificação , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/farmacologia , Regulação Bacteriana da Expressão Gênica , Genes Bacterianos , Dados de Sequência Molecular , Peptídeos/química , Peptídeos/isolamento & purificação , Biossíntese de Proteínas , Staphylococcus aureus/crescimento & desenvolvimento , Tiazóis/química , Tiazóis/isolamento & purificação
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