| Literature DB >> 33191745 |
Yang Liu1,2, Joseph M Eckenrode1, Yinan Zhang1,2, Jianjun Zhang1,2, Reiya C Hayden1, Annet Kyomuhangi1, Larissa V Ponomareva1,2, Zheng Cui1, Jürgen Rohr1, Oleg V Tsodikov1, Steven G Van Lanen1, Khaled A Shaaban1,2, Markos Leggas1,2, Jon S Thorson1,2.
Abstract
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.Entities:
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Year: 2020 PMID： 33191745 PMCID： PMC7810150 DOI： 10.1021/acs.jmedchem.0c01526
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446