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Bioorg Chem ; 149: 107504, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38850783

RESUMO

The notable characteristics of recently emerged Antibody-Drug Conjugates (ADCs) encompass the targeting of Human Epidermal growth factor Receptor 2 (HER2) through monoclonal antibodies (mAbs) and a high ratio of drug to antibody (DAR). The achievements of Kadcyla® (T-DM1) and Enhertu® (T-Dxd) have demonstrated that HER2-targeting antibodies, such as trastuzumab, have shown to be competitive in terms of efficacy and price for development. Furthermore, with the arrival of T-Dxd and Trodelvy®, high-DAR (7-8) ADCs, which differ from the moderate DAR (3-4) ADCs that were formerly regarded as conventional, are being acknowledged for their worth. Following this trend of drug development, we endeavored to develop a high-DAR ADC using a straightforward approach involving the utilization of DM1, a highly potent substance, in combination with the widely recognized trastuzumab. To achieve a high DAR, DM1 was conjugated to reduced cysteine through the simple design and synthesis of various dimaleimide linkers with differing lengths. Using LC and MS analysis, we have demonstrated that our synthesis methodology is uncomplicated and efficacious, yielding trastuzumab-based ADCs that exhibit a remarkable degree of uniformity. These ADCs have been experimentally substantiated to exert an inhibitory effect on cancer cells in vitro, thus affirming their value as noteworthy additions to the realm of ADCs.


Assuntos
Ado-Trastuzumab Emtansina , Imunoconjugados , Receptor ErbB-2 , Trastuzumab , Humanos , Imunoconjugados/química , Imunoconjugados/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Ado-Trastuzumab Emtansina/química , Trastuzumab/química , Trastuzumab/farmacologia , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Maleimidas/química , Maleimidas/síntese química , Relação Dose-Resposta a Droga , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Relação Estrutura-Atividade , Maitansina/química , Maitansina/farmacologia , Maitansina/síntese química , Maitansina/análogos & derivados , Linhagem Celular Tumoral , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/síntese química , Antineoplásicos Imunológicos/farmacologia
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