Mithramycin 2′-Oximes with Improved Selectivity, Pharmacokinetics, and Ewing Sarcoma Antitumor Efficacy,Journal of Medicinal Chemistry

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Mithramycin 2′-Oximes with Improved Selectivity, Pharmacokinetics, and Ewing Sarcoma Antitumor Efficacy
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-11-16 , DOI: 10.1021/acs.jmedchem.0c01526
Yang Liu _{1,

2} , Joseph M Eckenrode ₁ , Yinan Zhang _{1,

2} , Jianjun Zhang _{1,

2} , Reiya C Hayden ₁ , Annet Kyomuhangi ₁ , Larissa V Ponomareva _{1,

2} , Zheng Cui ₁ , Jürgen Rohr ₁ , Oleg V Tsodikov ₁ , Steven G Van Lanen ₁ , Khaled A Shaaban _{1,

2} , Markos Leggas _{1,

2} , Jon S Thorson _{1,

2}

Affiliation

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 (MTM_ox) conjugation strategy for rapid MTM diversification. Comparative cytotoxicity assays of 41 MTM_ox 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 MTM_ox32E (a Phe–Trp dipeptide-based 2′-conjugate) for in vivo testing. Relative to MTM, MTM_ox32E 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.

中文翻译：

具有改进的选择性、药代动力学和尤文肉瘤抗肿瘤功效的光神霉素 2'-肟

Mithramycin A (MTM) 抑制尤文肉瘤中的致癌转录因子 EWS-FLI1，但较差的药代动力学 (PK) 和毒性限制了其临床应用。为了解决这个限制，我们报告了一种有效的 MTM 2'-肟 (MTM _ox ) 共轭策略，用于快速 MTM 多样化。使用 E-26 (ETS) 融合依赖性和 ETS 融合非依赖性癌细胞系对 41 种 MTM _ox类似物进行的比较细胞毒性测定显示，与 MTM 相比，选择的 2'-偶联类似物的 ETS 非融合依赖性/依赖性选择性指数有所提高。基于荧光素酶的报告基因检测证明了低 nM 浓度下的靶标参与，分子检测显示类似物抑制 EWS-FLI1 的转录活性。这些体外筛选确定了MTM_ox 32 E（一种基于 Phe-Trp 二肽的 2'-偶联物）用于体内测试。相对于 MTM， MTM _ox 32 E在尤文肉瘤异种移植物中的血浆暴露增加了 11 倍，并提高了疗效。重要的是，这些研究首次指出 MTM 的简单 C3 脂肪族侧链修饰是改善 PK 的有效策略。

更新日期：2020-11-25

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