RESUMO
Inhibition of glutaminase-1 (GLS-1) hampers the proliferation of tumor cells reliant on glutamine. Known glutaminase inhibitors have potential limitations, and in vivo exposures are potentially limited due to poor physicochemical properties. We initiated a GLS-1 inhibitor discovery program focused on optimizing physicochemical and pharmacokinetic properties, and have developed a new selective inhibitor, compound 27 (IPN60090), which is currently in phase 1 clinical trials. Compound 27 attains high oral exposures in preclinical species, with strong in vivo target engagement, and should robustly inhibit glutaminase in humans.
Assuntos
Inibidores Enzimáticos/química , Glutaminase/antagonistas & inibidores , Triazóis/farmacocinética , Administração Oral , Animais , Linhagem Celular Tumoral , Cães , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Glutaminase/genética , Glutaminase/metabolismo , Meia-Vida , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Microssomos/metabolismo , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Relação Estrutura-Atividade , Triazóis/química , Triazóis/metabolismoRESUMO
Described are the syntheses of 14 derivatives of the natural product Sansalvamide A, where two are more active against HCT 116 colon cancer cell lines than the natural product. These derivatives were synthesized using a combinatorial-type strategy that permits elucidation of the amino acid role in the cytotoxicity, and they lay the groundwork for development of new anticancer agents. [structure: see text]
Assuntos
Antineoplásicos , Depsipeptídeos , Fusarium/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Depsipeptídeos/síntese química , Depsipeptídeos/química , Depsipeptídeos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Holliday junctions (HJs) are formed as transient DNA intermediates during site-specific and homologous recombination. Both of these genetic exchange pathways are critical for normal DNA metabolism and repair. Trapping HJs leads to bacterial cell death by preventing proper segregation of the resulting interlinked chromosomes. Macrocyclic peptides designed to target this intermediate were synthesized with the goal of identifying compounds with specificity for this unique molecular target. We discovered ten macrocycles, both hexameric and octameric peptides, capable of trapping HJs in vitro. Those macrocycles containing tyrosine residues proved most effective. These data demonstrate that C-2 symmetrical macrocycles offer excellent synthetic targets for the development of novel antibiotic agents. Furthermore, the active compounds identified provide valuable tools for probing different pathways of recombinational exchange.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , DNA Cruciforme/efeitos dos fármacos , DNA Cruciforme/metabolismo , Endodesoxirribonucleases/metabolismo , Proteínas de Escherichia coli/metabolismo , Oligopeptídeos/síntese química , Oligopeptídeos/farmacologia , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/farmacologia , Antibacterianos/química , Escherichia coli/efeitos dos fármacos , Escherichia coli/enzimologia , Técnicas In Vitro , Substâncias Macromoleculares , Modelos Moleculares , Estrutura Molecular , Conformação de Ácido Nucleico , Oligopeptídeos/química , Peptídeos Cíclicos/química , Conformação Proteica , Staphylococcus epidermidis/efeitos dos fármacosRESUMO
We report the synthesis of thirty-six Sansalvamide A derivatives, and their biological activity against colon cancer HT-29 cell line, a microsatellite stable (MSS) colon cancer cell-line. The thirty-six compounds can be divided into three subsets, where the first subset of compounds contains L-amino acids, the second subset contains D-amino acids, and the third subset contains both D- and L-amino acids. Five compounds exhibited excellent inhibitory activity (>75% inhibition). The structure-activity relationship (SAR) of the compounds established that a single D-amino acid in position 2 or 3 gave up to a 10-fold improved cytotoxicity over Sansalvamide A peptide. This work highlights the importance of residues 2 and 3 and the role of D-amino acids in the extraordinary SAR for this compound class.