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1.
J Med Chem ; 64(8): 4532-4552, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33822606

RESUMO

Prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II (GCPII), is a suitable target for specific delivery of antitumor drugs and diagnostic agents due to its overexpression in prostate cancer cells. In the current work, we describe the design, synthesis, and biological evaluation of novel low-molecular PSMA ligands and conjugates with fluorescent dyes FAM-5, SulfoCy5, and SulfoCy7. In vitro evaluation of synthesized PSMA ligands on the activity of PSMA shows that the addition of aromatic amino acids into a linker structure leads to a significant increase in inhibition. The conjugates of the most potent ligand with FAM-5 as well as SulfoCy5 demonstrated high affinities to PSMA-expressing tumor cells in vitro. In vivo biodistribution in 22Rv1 xenografts in Balb/c nude mice of PSMA-SulfoCy5 and PSMA-SulfoCy7 conjugates with a novel PSMA ligand demonstrated good visualization of PSMA-expressing tumors. Also, the conjugate PSMA-SulfoCy7 demonstrated the absence of any explicit toxicity up to 87.9 mg/kg.


Assuntos
Antígenos de Superfície/metabolismo , Antineoplásicos/metabolismo , Corantes Fluorescentes/química , Glutamato Carboxipeptidase II/metabolismo , Ligantes , Animais , Antígenos de Superfície/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Glutamato Carboxipeptidase II/química , Humanos , Masculino , Camundongos , Camundongos Nus , Imagem Óptica , Neoplasias da Próstata/tratamento farmacológico , Relação Estrutura-Atividade , Distribuição Tecidual , Transplante Heterólogo
2.
Nat Biotechnol ; 37(9): 1038-1040, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31477924

RESUMO

We have developed a deep generative model, generative tensorial reinforcement learning (GENTRL), for de novo small-molecule design. GENTRL optimizes synthetic feasibility, novelty, and biological activity. We used GENTRL to discover potent inhibitors of discoidin domain receptor 1 (DDR1), a kinase target implicated in fibrosis and other diseases, in 21 days. Four compounds were active in biochemical assays, and two were validated in cell-based assays. One lead candidate was tested and demonstrated favorable pharmacokinetics in mice.


Assuntos
Aprendizado Profundo , Receptor com Domínio Discoidina 1/antagonistas & inibidores , Receptor com Domínio Discoidina 1/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Animais , Receptor com Domínio Discoidina 1/genética , Cães , Inibidores Enzimáticos , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Ratos
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