RESUMO
Identifying isoform-specific inhibitors for closely related kinase family members remains a substantial challenge. The necessity for achieving this specificity is exemplified by the RSK family, downstream effectors of ERK1/2, which have divergent physiological effects. The natural product, SL0101, a flavonoid glycoside, binds specifically to RSK1/2 through a binding pocket generated by an extensive conformational rearrangement within the RSK N-terminal kinase domain (NTKD). In modelling experiments a single amino acid that is divergent in RSK3/4 most likely prevents the required conformational rearrangement necessary for SL0101 binding. Kinetic analysis of RSK2 association with SL0101 and its derivatives identified that regions outside of the NTKD contribute to stable inhibitor binding. An analogue with an n-propyl-carbamate at the 4" position on the rhamnose moiety was identified that forms a highly stable inhibitor complex with RSK2 but not with RSK1. These results identify a SL0101 modification that will aid the identification of RSK2 specific inhibitors.
Assuntos
Benzopiranos/síntese química , Monossacarídeos/síntese química , Inibidores de Proteínas Quinases/síntese química , Proteínas Quinases S6 Ribossômicas 90-kDa/antagonistas & inibidores , Sequência de Aminoácidos , Benzopiranos/metabolismo , Carbamatos/química , Humanos , Cinética , Modelos Moleculares , Monossacarídeos/metabolismo , Ligação Proteica , Conformação Proteica , Inibidores de Proteínas Quinases/metabolismo , Ramnose/química , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Relação Estrutura-AtividadeRESUMO
A series of E-ring lactone-opened camptothecin (CPT) derivatives bearing with terminal aza-heterocyclic groups were synthesized, and their antitumor activity was evaluated both in vitro and in vivo. Hydroxyl-amide analogues with morpholin-4-yl displayed excellent antitumor activity in vitro and efficient inhibition on tumor xenograph model in nude mice. Ester-amide compounds acted less active in vitro cytotoxicity and lower inhibition activity in vivo. Substitutions at 7- and 10- positions favored the antitumor activity.
Assuntos
Antineoplásicos Fitogênicos/síntese química , Camptotecina/análogos & derivados , Animais , Antineoplásicos Fitogênicos/farmacologia , Camptotecina/síntese química , Linhagem Celular Tumoral , Humanos , Camundongos , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Inhibition of the S-adenosyl methionine (SAM)-producing metabolic enzyme, methionine adenosyltransferase 2A (MAT2A), has received significant interest in the field of medicinal chemistry due to its implication as a synthetic lethal target in cancers with the deletion of the methylthioadenosine phosphorylase (MTAP) gene. Here, we report the identification of novel MAT2A inhibitors with distinct in vivo properties that may enhance their utility in treating patients. Following a high-throughput screening, we successfully applied the structure-based design lessons from our first-in-class MAT2A inhibitor, AG-270, to rapidly redesign and optimize our initial hit into two new lead compounds: a brain-penetrant compound, AGI-41998, and a potent, but limited brain-penetrant compound, AGI-43192. We hope that the identification and first disclosure of brain-penetrant MAT2A inhibitors will create new opportunities to explore the potential therapeutic effects of SAM modulation in the central nervous system (CNS).
Assuntos
Metionina Adenosiltransferase , Neoplasias , Encéfalo/metabolismo , Desenho de Fármacos , Humanos , Neoplasias/tratamento farmacológico , S-Adenosilmetionina/metabolismoRESUMO
A novel Pd-catalyzed decarboxylative ortho-acylation of acetanilides with alpha-oxocarboxylic acids is realized at room temperature. This reaction provides efficient access to o-acyl acetanilides under mild conditions.
Assuntos
Acetanilidas/química , Ácidos Carboxílicos/química , Cetonas/síntese química , Compostos Organometálicos/química , Paládio/química , Temperatura , Catálise , Descarboxilação , Cetonas/química , Estrutura Molecular , EstereoisomerismoRESUMO
An asymmetric synthesis of two analogues of SL0101 (1) has been achieved. The effort is aimed at the discovery of inhibitors of the p90 ribosomal S6 kinase (RSK) with improved bioavailability. The route relies upon the use of the Taylor catalyst to regioselectively install C-3â³ acetyl or carbamate functionality. This study led to the identification of a third-generation analogue of SL0101 with a C-4â³ n-Pr-carbamate and a C-3â³ acetate with improved RSK inhibitory activity.
Assuntos
Benzopiranos/farmacologia , Monossacarídeos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases S6 Ribossômicas 90-kDa/antagonistas & inibidores , Benzopiranos/síntese química , Benzopiranos/química , Estrutura Molecular , Monossacarídeos/síntese química , Monossacarídeos/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , EstereoisomerismoRESUMO
A series of 7-cycloalkylcamptothecin derivatives were synthesized from camptothecin with two methods. Their biological activities in vitro were evaluated with sulforhodamine-B (SRB) method on four types of human tumor cell lines A549/ATCC, HT29, NCI-H460 and HL60. Most of these camptothecin analogues show higher antitumor activity than the reference compounds SN-38 and Topotecan, with the IC(50) values low to nM level. Structure-activity relationship studies of these compounds mostly match the conclusion we achieved before from quantitative structure-activity relationship (QSAR) research.
Assuntos
Camptotecina/administração & dosagem , Camptotecina/síntese química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Neoplasias Colorretais/tratamento farmacológico , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Humanos , Hidrólise , Concentração Inibidora 50 , Irinotecano , Modelos Químicos , Rodaminas/farmacologia , Relação Estrutura-Atividade , Topotecan/síntese química , Topotecan/farmacologiaRESUMO
A series of E-ring gamma-lactone camptothecin derivatives were synthesized by semi-synthesis via a three-step domino reaction. Their biological activity was evaluated on two types of human tumor cell lines A549 and HT-29 with sulforhodamine-B (SRB) method. The antitumor activity of these compounds was lower than SN-38, only compound 12c was found to be close to the activity of Topotecan. The structure-activity relationship (SAR) of these analogs was studied and discussed.
Assuntos
Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/farmacologia , Camptotecina/síntese química , Camptotecina/farmacologia , Lactonas/química , Antineoplásicos Fitogênicos/uso terapêutico , Camptotheca/metabolismo , Camptotecina/análogos & derivados , Camptotecina/química , Linhagem Celular Tumoral , DNA Topoisomerases Tipo I/metabolismo , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Irinotecano , Modelos Químicos , Estrutura Molecular , Solubilidade , Relação Estrutura-AtividadeRESUMO
A convergent synthesis of 5a-carbasugar analogues of the n-Pr-variant of SL0101 is described. The analogues were synthesized in an effort to find compounds with potent in vivo efficacy in the inhibition of p90 ribosomal s6 kinase (RSK1/2). The synthesis derived the desired C-4 L-rhamnose stereochemistry from quinic acid and used a highly selective cuprate addition, NaBH4 reduction, Mitsunobu inversion, and alkene dihydroxylation to install the remaining stereochemistry. A Pd-catalyzed cyclitolization stereoselectively installed the aglycon at the anomeric position. The analogues were evaluated as RSK1/2 inhibitors and found to have 3- to 6-fold improved activity.
RESUMO
Metastatic breast cancer is an incurable disease and identification of novel therapeutic opportunities is vital. Triple-negative breast cancer (TNBC) frequently metastasizes and high levels of activated p90RSK (RSK), a downstream MEK-ERK1/2 effector, are found in TNBC. We demonstrate, using direct pharmacologic and genetic inhibition of RSK1/2, that these kinases contribute to the TNBC metastatic process in vivo Kinase profiling showed that RSK1 and RSK2 are the predominant kinases targeted by the new inhibitor, which is based on the natural product SL0101. Further evidence for selectivity was provided by the observations that silencing RSK1 and RSK2 eliminated the ability of the analogue to further inhibit survival or proliferation of a TNBC cell line. In vivo, the new derivative was as effective as the FDA-approved MEK inhibitor trametinib in reducing the establishment of metastatic foci. Importantly, inhibition of RSK1/2 did not result in activation of AKT, which is known to limit the efficacy of MEK inhibitors in the clinic. Our results demonstrate that RSK is a major contributor to the TNBC metastatic program and provide preclinical proof-of-concept for the efficacy of the novel SL0101 analogue in vivo Mol Cancer Ther; 15(11); 2598-608. ©2016 AACR.
Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases S6 Ribossômicas 90-kDa/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Antineoplásicos/química , Benzopiranos/química , Benzopiranos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Feminino , Inativação Gênica , Humanos , Camundongos , Monossacarídeos/química , Monossacarídeos/farmacologia , Metástase Neoplásica , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The Ser/Thr protein kinase, RSK, is associated with oncogenesis, and therefore, there are ongoing efforts to develop RSK inhibitors that are suitable for use in vivo. SL0101 is a natural product that demonstrates selectivity for RSK inhibition. However, SL0101 has a short biological half-life in vivo. To address this issue we designed a set of eight cyclitol analogues, which should be resistant to acid catalyzed anomeric bond hydrolysis. The analogues were synthesized and evaluated for their ability to selectively inhibit RSK in vitro and in cell-based assays. All the analogues were prepared using a stereodivergent palladium-catalyzed glycosylation/cyclitolization for installing the aglycon. The l-cyclitol analogues were found to inhibit RSK2 in in vitro kinase activity with a similar efficacy to that of SL0101, however, the analogues were not specific for RSK in cell-based assays. In contrast, the d-isomers showed no RSK inhibitory activity in in vitro kinase assay.
RESUMO
A novel Pd-catalyzed decarboxylative cross-coupling of potassium aryltrifluoroborates with α-oxocarboxylic acids is performed at room temperature. This reaction provides an efficient access to aryl ketones under mild conditions.
RESUMO
A novel Pd-catalyzed decarboxylative cross-coupling of oxamic acids with potassium phenyltrifluoroborates has been realized under mild reaction conditions. This method provides an efficient access to N-mono- or N,N-disubstituted benzamides and benzoates.
RESUMO
An efficient palladium-catalyzed decarboxylative acylation of unactivated arenes with alpha-oxocarboxylic acids is reported. This method provides a novel access to aryl ketones.