RESUMO
The work in this paper describes the optimization of the 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine chemical series as potent, selective allosteric inhibitors of AKT kinases, leading to the discovery of ARQ 092 (21a). The cocrystal structure of compound 21a bound to full-length AKT1 confirmed the allosteric mode of inhibition of this chemical class and the role of the cyclobutylamine moiety. Compound 21a demonstrated high enzymatic potency against AKT1, AKT2, and AKT3, as well as potent cellular inhibition of AKT activation and the phosphorylation of the downstream target PRAS40. Compound 21a also served as a potent inhibitor of the AKT1-E17K mutant protein and inhibited tumor growth in a human xenograft mouse model of endometrial adenocarcinoma.
Assuntos
Aminopiridinas/farmacologia , Antineoplásicos/farmacologia , Carcinoma Endometrioide/tratamento farmacológico , Descoberta de Drogas , Neoplasias do Endométrio/tratamento farmacológico , Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Administração Oral , Regulação Alostérica/efeitos dos fármacos , Aminopiridinas/administração & dosagem , Aminopiridinas/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Carcinoma Endometrioide/patologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias do Endométrio/patologia , Feminino , Humanos , Imidazóis/administração & dosagem , Imidazóis/química , Camundongos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Relação Estrutura-AtividadeRESUMO
This paper describes the implementation of a biochemical and biophysical screening strategy to identify and optimize small molecule Akt1 inhibitors that act through a mechanism distinct from that observed for kinase domain ATP-competitive inhibitors. With the aid of an unphosphorylated Akt1 cocrystal structure of 12j solved at 2.25 Å, it was possible to confirm that as a consequence of binding these novel inhibitors, the ATP binding cleft contained a number of hydrophobic residues that occlude ATP binding as expected. These Akt inhibitors potently inhibit intracellular Akt activation and its downstream target (PRAS40) in vitro. In vivo pharmacodynamic and pharmacokinetic studies with two examples, 12e and 12j, showed the series to be similarly effective at inhibiting the activation of Akt and an additional downstream effector (p70S6) following oral dosing in mice.
Assuntos
Trifosfato de Adenosina/fisiologia , Antineoplásicos/síntese química , Imidazóis/síntese química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Piridinas/síntese química , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Disponibilidade Biológica , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Imidazóis/química , Imidazóis/farmacologia , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Fosforilação , Ligação Proteica , Conformação Proteica , Piridinas/química , Piridinas/farmacologia , Proteínas Quinases S6 Ribossômicas 70-kDa/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
New arylpiperazines related to buspirone, gepirone and NAN-190 were designed and screened in silico for their 5-HT(1A) affinity and potential sites of metabolism by human cytochrome p450 (CYP3A4). Modifications to these structures were assessed in silico for their influence on both 5HT(1A) affinity and metabolism. Selected new molecules were synthesized and purified in a parallel chemistry approach to determine structure activity relationships (SARs). The resulting molecules were assessed in vitro for their 5HT(1A) affinity and half-life in a heterologously expressed human CYP3A4 assay. Molecular features responsible for 5-HT(1A) affinity and CYP3A4 stability are described.
Assuntos
Desenho de Fármacos , Piperazinas/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Serotoninérgicos/metabolismo , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Ligantes , Piperazinas/síntese química , Serotoninérgicos/síntese químicaRESUMO
Calix[4]arenes, calix[4]resorcarenes, and anionic cyclodextrin derivatives were examined as chiral NMR solvating agents. The calix[4]arenes were prepared by attachment of amino acids through the hydroxyl groups of the phenol rings. Chloroform-, methanol-, and water-soluble derivatives were prepared and tested with a range of substrates. Chloroform-soluble chiral calix[4]resorcarenes were prepared by attachment of chiral primary and secondary amines and examined in NMR applications with a variety of substrates. Sulfated and carboxymethylated beta-cyclodextrin are effective at causing enantiomeric discrimination in the (1)H NMR spectra of organic cations. Lanthanide ions associate at the carboxymethyl groups and cause sizeable shifts and enhancements in enantiomeric discrimination in the spectra of organic cations. The enhancements caused by the lanthanide ion are large enough that much lower concentrations of the cyclodextrin can be used as compared to conventional analyses.