Mithramycin 2'-Oximes with Improved Selectivity, Pharmacokinetics, and Ewing Sarcoma Antitumor Efficacy.

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.

• Authors: Yang Liu, Joseph M Eckenrode, Yinan Zhang, Jianjun Zhang, Reiya C Hayden, Annet Kyomuhangi, Larissa V Ponomareva, Zheng Cui, Jürgen Rohr, Oleg V Tsodikov, Steven G Van Lanen, Khaled A Shaaban, Markos Leggas, Jon S Thorson
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 63 Issue 22 Pg. 14067-14086 (11 25 2020) ISSN: 1520-4804 [Electronic] United States
• PMID: 33191745 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Oximes
• Plicamycin

Topics

• Animals
• Antibiotics, Antineoplastic (chemistry, pharmacokinetics, pharmacology)
• Apoptosis
• Bone Neoplasms (drug therapy, pathology)
• Cell Proliferation
• Female
• Humans
• Mice
• Mice, SCID
• Oximes (chemistry)
• Plicamycin (chemistry)
• Sarcoma, Ewing (drug therapy, pathology)
• Tissue Distribution
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays