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J Med Chem ; 63(22): 14067-14086, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33191745

RESUMO

Mithramycin A (MTM) inhibits the oncogenic transcription factor EWS-FLI1 in Ewing sarcoma, but poor pharmacokinetics (PK) and toxicity limit its clinical use. To address this limitation, we report an efficient MTM 2'-oxime (MTMox) conjugation strategy for rapid MTM diversification. Comparative cytotoxicity assays of 41 MTMox analogues using E-twenty-six (ETS) fusion-dependent and ETS fusion-independent cancer cell lines revealed improved ETS fusion-independent/dependent selectivity indices for select 2'-conjugated analogues as compared to MTM. Luciferase-based reporter assays demonstrated target engagement at low nM concentrations, and molecular assays revealed that analogues inhibit the transcriptional activity of EWS-FLI1. These in vitro screens identified MTMox32E (a Phe-Trp dipeptide-based 2'-conjugate) for in vivo testing. Relative to MTM, MTMox32E displayed an 11-fold increase in plasma exposure and improved efficacy in an Ewing sarcoma xenograft. Importantly, these studies are the first to point to simple C3 aliphatic side-chain modification of MTM as an effective strategy to improve PK.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Antibióticos Antineoplásicos/farmacocinética , Neoplasias Ósseas/tratamento farmacológico , Oximas/química , Plicamicina/química , Sarcoma de Ewing/tratamento farmacológico , Animais , Antibióticos Antineoplásicos/química , Apoptose , Neoplasias Ósseas/patologia , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos SCID , Sarcoma de Ewing/patologia , Distribuição Tecidual , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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