RESUMO
A series of 5-ureidobenzofuranones was discovered as potent and selective inhibitors of mTOR with good cellular activity. Molecular modeling studies revealed several hydrogen bond interactions of the ureido group with the enzyme at the ATP-binding site. Furthermore, modeling showed that the ureido group is best situated at C-5 of the benzofuranone. Syntheses of 4-ureido and 5-ureidobenzofuranones are presented.
Assuntos
Trifosfato de Adenosina/metabolismo , Benzofuranos/química , Benzofuranos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Classe Ib de Fosfatidilinositol 3-Quinase , Cristalografia por Raios X , Humanos , Ligação de Hidrogênio , Peptídeos e Proteínas de Sinalização Intracelular/química , Isoenzimas/química , Modelos Moleculares , Fosfatidilinositol 3-Quinases/química , Proteínas Serina-Treonina Quinases/química , Sirolimo , Homologia Estrutural de Proteína , Serina-Treonina Quinases TORRESUMO
We discovered 2-(4-substituted-pyrrolo[2,3-b]pyridin-3-yl)methylene-4-hydroxybenzofuran-3(2H)-ones as potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR). Since phenolic OH groups pose metabolic liability, one of the two hydroxyl groups was selectively removed. The SAR data showed the structural features necessary for subnanomolar inhibitory activity against mTOR kinase as well as selectivity over PI3Kalpha. An X-ray co-crystal structure of one inhibitor with the mTOR-related PI3Kgamma revealed the key hydrogen bonding interactions.
Assuntos
Benzofuranos/química , Benzofuranos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Cristalografia por Raios X , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Nus , Microssomos/metabolismo , Modelos Moleculares , Neoplasias/tratamento farmacológico , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/metabolismo , Relação Estrutura-Atividade , Serina-Treonina Quinases TORRESUMO
The series of 4-(benzylaminomethylene)isoquinoline-1,3-(2H,4H)-dione and 4-[(pyridylmethyl)aminomethylene]isoquinoline-1,3-(2H,4H)-dione derivatives reported here represents a novel class of potential antitumor agents, which potently and selectively inhibit CDK4 over CDK2 and CDK1. In the benzylamino headpiece, a 3-OH substituent is required on the phenyl ring for CDK4 inhibitory activity, which is further enhanced when an iodo, aryl, heteroaryl, t-butyl, or cyclopentyl substituent is introduced at the C-6 position of the isoquinoline-1,3-dione core. To circumvent the metabolic liability associated with the phenolic OH group on the 4-substituted 3-OH phenyl headpiece, we take two approaches: first, introduce a nitrogen o- or p- to the 3-OH group in the phenyl ring; second, replace the phenyl headpiece with N-substituted 2-pyridones. We present here the synthesis, SAR data, metabolic stability data, and a CDK4 mimic model that explains the binding, potency, and selectivity of our CDK4 selective inhibitors.
Assuntos
Antineoplásicos/síntese química , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Isoquinolinas/síntese química , Piridinas/síntese química , Trifosfato de Adenosina/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligação de Hidrogênio , Técnicas In Vitro , Isoquinolinas/química , Isoquinolinas/farmacologia , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Fosforilação , Piridinas/química , Piridinas/farmacologia , Ratos , Proteína do Retinoblastoma/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The cyclin-dependent kinases (CDKs), as complexes with their respective partners, the cyclins, are critical regulators of cell cycle progression. Because aberrant regulations of CDK4/cyclin D1 lead to uncontrolled cell proliferation, a hallmark of cancer, small-molecule inhibitors of CDK4/cyclin D1 are attractive as prospective antitumor agents. The series of 4-(phenylaminomethylene)isoquinoline-1,3(2H,4H)-dione derivatives reported here represents a novel class of potent inhibitors that selectively inhibit CDK4 over CDK2 and CDK1 activities. In the headpiece of the 4-(phenylaminomethylene)isoquinoline-1,3(2H,4H)-dione, a basic amine substituent is required on the aniline ring for the CDK4 inhibitory activity. The inhibitory activity is further enhanced when an aryl or heteroaryl substituent is introduced at the C-6 position of the isoquinoline-1,3(2H,4H)-dione core. We present here SAR data and a CDK4 mimic model that explains the binding, potency, and selectivity of our CDK4 selective inhibitors.
Assuntos
Antineoplásicos/síntese química , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Isoquinolinas/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isoquinolinas/química , Isoquinolinas/farmacologia , Modelos Moleculares , Fosforilação , Proteína do Retinoblastoma/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
It has been previously reported that appropriately substituted 4-anilinoquinoline-3-carbonitriles are potent inhibitors of Src kinase, with biological activity in vitro and in vivo. Structural modifications to these compounds have been explored, providing the 4-anilinobenzo[g]quinoline-3-carbonitriles as a series with enhanced Src inhibitory properties. The synthesis and structure-activity relationships of these 4-anilino-7,8-dialkoxybenzo[g]quinoline-3-carbonitriles are presented here. Analogues with cyclic basic amine groups attached via ethoxy linkages at the C-8 position were the most active in vitro, with subnanomolar IC50 values against Src kinase observed for a majority of the compounds synthesized. Compound 17d was more potent in vitro than the analogously substituted 4-anilinoquinoline-3-carbonitrile SKI-606, which is undergoing evaluation in clinical trials. The most potent analogue synthesized was 17a, with an IC50 of 0.15 nM against Src kinase and with an IC50 of 10 nM against Src-transformed fibroblasts. Molecular modeling studies provided a rationale for the exceptional activity observed for these compounds, with favorable van der Waals interactions playing the major role. Compound 17c was found to be highly selective for Src kinase when tested against a panel of other kinases, with modest selectivity versus the Src family kinases Lyn and Fyn. Following ip dosing at 50 mg/kg, analogues 17c and 17d were shown to have plasma levels that significantly exceeded the cellular IC50 values against Src-transformed fibroblasts. In an Src-transformed fibroblast xenograft model, both compounds exhibited a significant inhibition of tumor growth.
Assuntos
Compostos de Anilina/síntese química , Antineoplásicos/síntese química , Nitrilas/síntese química , Quinolinas/síntese química , Quinases da Família src/antagonistas & inibidores , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Sítios de Ligação , Disponibilidade Biológica , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica , Fibroblastos/patologia , Humanos , Camundongos , Modelos Moleculares , Nitrilas/química , Nitrilas/farmacologia , Fosforilação , Quinolinas/química , Quinolinas/farmacologia , Ratos , Relação Estrutura-Atividade , Tirosina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases da Família src/metabolismoRESUMO
Hemiasterlin, a tripeptide isolated from marine sponges, induces microtubule depolymerization and mitotic arrest in cells. HTI-286, an analogue from an initial study of the hemiasterlins, is presently in clinical trials. In addition to its potent antitumor effects, 2 has the advantage of circumventing the P-glycoprotein-mediated resistance that hampers the efficacy of other antimicrotubule agents such as paclitaxel and vincristine in animal models. This paper describes an in-depth study of the structure--activity relationships of analogues of 2, their effects on microtubule polymerization, and their in vitro and in vivo anticancer activity. Regions of the molecule necessary for potent activity are identified. Groups tolerant of modification, leading to novel analogues, are reported. Potent analogues identified through in vivo studies in tumor xenograft models include one superior analogue, HTI-042.
Assuntos
Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Aminas/química , Animais , Morte Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Ciclização , Ésteres/química , Humanos , Concentração Inibidora 50 , Metilaminas/síntese química , Metilaminas/química , Camundongos , Microtúbulos/química , Estrutura Molecular , Neoplasias/patologia , Oligopeptídeos/síntese química , Oxirredução , Peptídeos/síntese química , Peptídeos/química , Ácido Pirúvico/química , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismoRESUMO
Modifications of the D-piece carboxylic acid group of the hemiasterlin analog HTI-286 gave tubulin inhibitors which were potent cytotoxic agents in taxol resistant cell lines expressing P-glycoprotein. Amides derived from proline had potency comparable to HTI-286. Reduction of the carboxylic acid to ketones and alcohols or its conversion to acidic heterocycles also gave potent analogs. Synthetic modifications of the carboxylic acid could be carried out selectively using a wide range of synthetic reagents. Proline analog 3 was found to be effective in a human xenograft model in athymic mice.