Design and Synthesis of 7-Oxabicyclo[2.2.1]heptane-2,3-dicarboxylic Acid Derivatives as PP5 Inhibitors To Reverse Temozolomide Resistance in Glioblastoma Multiforme,Journal of Medicinal Chemistry

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Design and Synthesis of 7-Oxabicyclo[2.2.1]heptane-2,3-dicarboxylic Acid Derivatives as PP5 Inhibitors To Reverse Temozolomide Resistance in Glioblastoma Multiforme
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-13 , DOI: 10.1021/acs.jmedchem.4c01304
Zekun Li _{1,

2} , Mochen Guo _{1,

2} , Mingxiao Gu _{1,

2} , Zhongtian Cai _{1,

2} , Qiuyu Wu _{1,

2} , Jia Yu _{1,

2} , Meilun Tang _{1,

2} , Chenxi He _{1,

2} , Yuxuan Wang _{1,

2} , Piaoyang Sun ₃ , Qidong You _{1,

2} , Lei Wang _{1,

2}

Affiliation

The serine/threonine phosphatase family is important in tumor progression and survival. Due to the high conserved catalytic domain, designing selective inhibitors is challenging. Herein, we obtained compound 28a with 38-fold enhanced PP5 selectivity (PP2A/5 IC₅₀ = 33.8/0.9 μM) and improved drug-like properties (favorable stability and safety, F = 82.0%) by rational drug design based on a phase II PP2A/5 dual target inhibitor LB-100. Importantly, we found the spatial conformational restriction of the 28a indole fragment was responsible for the selectivity of PP5. Thus, 28a activated p53 and downregulated cyclin D1 and MGMT, which showed potency in cell cycle arrest and reverse temozolomide (TMZ) resistance in the U87 MG cell line. Furthermore, oral administration of 28a and TMZ was well tolerated to effectively inhibit tumor growth (TGI = 87.7%) in the xenograft model. Collectively, these results implicate 28a could be a drug candidate by reversing TMZ resistance with a selective PP5 inhibition manner.

中文翻译：

设计和合成 7-氧杂双环[2.2.1]庚烷-2,3-二甲酸衍生物作为 PP5 抑制剂以逆转多形性胶质母细胞瘤中的替莫唑胺耐药性

丝氨酸/苏氨酸磷酸酶家族对于肿瘤进展和存活很重要。由于催化结构域高度保守，设计选择性抑制剂具有挑战性。在此，我们通过基于相的合理药物设计，获得了化合物28a ，其PP5选择性提高了38倍（PP2A/5 IC ₅₀ = 33.8/0.9 μM）并改善了类药特性（良好的稳定性和安全性， F = 82.0%） II PP2A/5双靶点抑制剂LB-100 。重要的是，我们发现28a吲哚片段的空间构象限制是造成 PP5 选择性的原因。因此， 28a激活 p53 并下调细胞周期蛋白 D1 和 MGMT，这在 U87 MG 细胞系中显示出细胞周期停滞和逆转替莫唑胺 (TMZ) 耐药性的功效。此外，口服28a和TMZ的耐受性良好，可有效抑制异种移植模型中的肿瘤生长（TGI = 87.7%）。总的来说，这些结果表明28a可能是通过选择性 PP5 抑制方式逆转 TMZ 耐药性的候选药物。

更新日期：2024-08-13

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