RESUMO
The docking approach for the screening of designed small molecule ligands, led to the identification of a critical arginine residue in peptide deformylase for spiro cyclopropyl PDF inhibitor's extra hydrophobic binding, providing us a useful tool for searching more efficient PDF inhibitors to fight for horrifying antibiotics resistance. Further synthetic modification was undertaken to optimize the potency of amide compounds. To lower metabolic susceptibility and in turn reduce unwanted metabolic toxicity that was observed clinically, while retaining desired antibacterial activity, the use of azoles as amide bioisosteres had also been investigated. After the completion of chemical synthesis, all the compounds were evaluated through in vitro antibacterial activity assay, some of which were further subject to in vivo rat pharmacokinetic assessment. Those findings in this letter showed that spiro cyclopropyl proline N-formyl hydroxylamines, and especially the bioisosteric azoles, can represent a promising class of PDF inhibitors.
Assuntos
Amidoidrolases/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Amidoidrolases/metabolismo , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/síntese química , Humanos , Masculino , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Alpha-dystroglycan (α-DG), a highly glycosylated receptor for extracellular matrix proteins, plays a critical role in many biological processes. Hypoglycosylation of α-DG results in various types of muscular dystrophies and is also highly associated with progression of majority of cancers. Currently, there are no effective treatments for those devastating diseases. Enhancing functional O-mannosyl glycans (FOG) of α-DG on the cell surfaces is a potential approach to address this unmet challenge. Based on the hypothesis that the cells can up-regulate FOG of α-DG in response to certain chemical stimuli, we developed a cell-based high-throughput screening (HTS) platform for searching chemical enhancers of FOG of α-DG from a large chemical library with 364,168 compounds. Sequential validation of the hits from a primary screening campaign and chemical works led to identification of a cluster of compounds that positively modulate FOG of α-DG on various cell surfaces including patient-derived myoblasts. These compounds enhance FOG of α-DG by almost ten folds, which provide us powerful tools for O-mannosylation studies and potential starting points for the development of drug to treat dystroglycanopathy.
Assuntos
Distroglicanas/metabolismo , Glicosilação/efeitos dos fármacos , Manose/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Células CHO , Linhagem Celular , Cricetulus , Avaliação Pré-Clínica de Medicamentos/métodos , Ensaios de Triagem em Larga Escala/métodos , Humanos , Camundongos , Distrofias Musculares/tratamento farmacológico , Distrofias Musculares/metabolismoRESUMO
The diastereoselectively switchable enantioselective trapping of protic carbamate ammonium ylides with imines is reported. The intriguing Rh(2)(OAc)(4) and chiral Brønsted acid cocatalyzed three-component Mannich-type reaction of a diazo compound, a carbamate, and an imine provides rapid and efficient access to both syn- and anti-α-substituted α,ß-diamino acid derivatives with a high level control of chemo-, diastereo-, and enantioselectivity.
Assuntos
Carbamatos/química , Iminas/química , Compostos de Amônio Quaternário/química , Catálise , Estrutura Molecular , Ácidos Fosfóricos/química , Ródio/química , EstereoisomerismoRESUMO
The RNA methyltransferase TRDMT1 has recently emerged as a key regulator of homologous recombination (HR) in the transcribed regions of the genome, but how it is regulated and its relevance in cancer remain unknown. Here, we identified that TRDMT1 is poly-ubiquitinated at K251 by the E3 ligase TRIM28, removing TRDMT1 from DNA damage sites and allowing completion of HR. Interestingly, K251 is adjacent to G155 in the 3D structure, and the G155V mutation leads to hyper ubiquitination of TRDMT1, reduced TRDMT1 levels and impaired HR. Accordingly, a TRDMT1 G155V mutation in an ovarian cancer super responder to platinum treatment. Cells expressing TRDMT1-G155V are sensitive to cisplatin in vitro and in vivo. In contrast, high expression of TRDMT1 in patients with ovarian cancer correlates with platinum resistance. A potent TRDMT1 inhibitor resensitizes TRDMT1-high tumor cells to cisplatin. These results suggest that TRDMT1 is a promising therapeutic target to sensitize ovarian tumors to platinum therapy.
RESUMO
Tropomyosin receptor kinase (TRK) represents an attractive oncology target for cancer therapy related to its critical role in cancer formation and progression. NTRK fusions are found to occur in 3.3% of lung cancers, 2.2% of colorectal cancers, 16.7% of thyroid cancers, 2.5% of glioblastomas, and 7.1% of pediatric gliomas. In this paper, we described the discovery of the type-II pan-TRK inhibitor 4c through the structure-based drug design strategy from the original hits 1b and 2b. Compound 4c exhibited excellent in vitro TRKA, TRKB, and TRKC kinase inhibitory activity and anti-proliferative activity against human colorectal carcinoma derived cell line KM12. In the NCI-60 human cancer cell lines screen, compound 4g demonstrated nearly 80% of growth inhibition for KM12, while only minimal inhibitory activity was observed for the remaining 59 cancer cell lines. Western blot analysis demonstrated that 4c and its urea cousin 4k suppressed the TPM3-TRKA autophosphorylation at the concentrations of 100 nM and 10 nM, respectively. The work presented that 2-(4-(thieno[3,2-d]pyrimidin-4-ylamino)phenyl)acetamides could serve as a novel scaffold for the discovery and development of type-II pan-TRK inhibitors for the treatment of TRK driven cancers.
Assuntos
Acetamidas/química , Desenho de Fármacos , Inibidores de Proteínas Quinases/síntese química , Receptor trkA/antagonistas & inibidores , Receptor trkB/antagonistas & inibidores , Acetamidas/metabolismo , Acetamidas/farmacologia , Sítios de Ligação , Barreira Hematoencefálica/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/química , Pirimidinas/química , Receptor trkA/metabolismo , Receptor trkB/metabolismo , Relação Estrutura-AtividadeRESUMO
The use of kinase-directed precision medicine has been heavily pursued since the discovery and development of imatinib. Annually, it is estimated that around â¼20â¯000 new cases of tropomyosin receptor kinase (TRK) cancers are diagnosed, with the majority of cases exhibiting a TRK genomic rearrangement. In this Perspective, we discuss current development and clinical applications for TRK precision medicine by providing the following: (1) the biological background and significance of the TRK kinase family, (2) a compilation of known TRK inhibitors and analysis of their cocrystal structures, (3) an overview of TRK clinical trials, and (4) future perspectives for drug discovery and development of TRK inhibitors.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Receptor trkA/antagonistas & inibidores , Receptor trkB/antagonistas & inibidores , Receptor trkC/antagonistas & inibidores , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Domínio Catalítico , Linhagem Celular Tumoral , Descoberta de Drogas , Humanos , Camundongos Endogâmicos BALB C , Medicina de Precisão/métodos , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Ratos Sprague-Dawley , Receptor trkA/química , Receptor trkA/metabolismo , Receptor trkB/química , Receptor trkB/metabolismo , Receptor trkC/química , Receptor trkC/metabolismoRESUMO
Peptide deformylase (PDF) has been identified as a promising target for novel antibacterial agents. In this study, a series of novel formyl hydroxyamino derivatives were designed and synthesized as PDF inhibitors and their antibacterial activities were evaluated. Among the potent PDF inhibitors (1o, 1q, 1o', 1q', and 1x), in vivo studies showed that compound 1q possesses mild toxicity, a good pharmacokinetic profile and protective effects. The good in vivo efficacy and low toxicity suggest that this class of compounds has potential for development and use in future antibacterial drugs.
Assuntos
Amidoidrolases/antagonistas & inibidores , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Farmacorresistência Bacteriana/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Oligopeptídeos/farmacologia , Amidoidrolases/metabolismo , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oligopeptídeos/síntese química , Oligopeptídeos/química , Relação Estrutura-AtividadeRESUMO
A highly enantioselective trapping of protic phosphoramidate ammonium ylides with α-imino esters is reported. The intriguing Rh2(OAc)4 and chiral Brønsted acid co-catalyzed three-component Mannich-type reaction of a diazo compound, a phosphoramidate, and an α-imino ester provides a rapid and efficient access to 2,3-diaminosuccinic acid derivatives with a high level control of diastereo- and enantioselectivity.
Assuntos
Amidas/química , Diamino Aminoácidos/química , Iminas/química , Ácidos Fosfóricos/química , Compostos de Amônio Quaternário/química , Diamino Aminoácidos/síntese química , Compostos Azo/química , Catálise , Complexos de Coordenação/química , Cristalografia por Raios X , Ésteres , Conformação Molecular , Ródio/química , EstereoisomerismoRESUMO
Reactions with the unstable and highly reactive zwitterionic intermediates generated in processes catalysed by transition metals are providing new opportunities for molecular constructions. Insertion reactions involve the collapse of zwitterionic intermediates, but trapping them would allow structural elaborations that are not currently available. To synthesize complex molecules in this manner, reactive electrophiles can be used to trap the zwitterionic intermediates. Here, we describe the use of imines, activated by chiral organocatalysts, and a highly efficient integrated rhodium and chiral Brønsted acid co-catalysed process to trap zwitterionic intermediates that have been proposed previously to undergo a formal C-H insertion reaction, allowing us to obtain polyfunctionalized indole and oxindole derivatives in a single step with excellent diastereoselectivity and enantioselectivity.