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

被引：0

作者：

Li, Zekun ^{[1
,2
,3
]}

Guo, Mochen ^{[1
,2
,3
]}

Gu, Mingxiao ^{[1
,2
,3
]}

Cai, Zhongtian ^{[1
,2
,3
]}

Wu, Qiuyu ^{[1
,2
,3
]}

Yu, Jia ^{[1
,2
,3
]}

Tang, Meilun ^{[1
,2
,3
]}

He, Chenxi ^{[1
,2
,3
]}

Wang, Yuxuan ^{[1
,2
,3
]}

Sun, Piaoyang ^{[4
]}

You, Qidong ^{[1
,2
,3
]}

Wang, Lei ^{[1
,2
,3
]}

机构：

[1] China Pharmaceut Univ, State Key Lab Nat Med, Nanjing 210009, Peoples R China

[2] China Pharmaceut Univ, Jiangsu Key Lab Drug Design & Optimizat, Nanjing 210009, Peoples R China

[3] China Pharmaceut Univ, Sch Pharm, Dept Med Chem, Nanjing 210009, Peoples R China

[4] Shanghai Hengrui Pharmaceut Co Ltd, Shanghai 200245, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2024年 / 67卷 / 17期

基金：

中国国家自然科学基金;

关键词：

SERINE/THREONINE PROTEIN PHOSPHATASES; RANDOMIZED PHASE-III; NORCANTHARIDIN ANALOGS; ADJUVANT TEMOZOLOMIDE; PANCREATIC-CANCER; POTENT INHIBITOR; STRUCTURAL BASIS; MICROCYSTIN-LR; CELL-GROWTH; CYCLIN D1;

D O I：

10.1021/acs.jmedchem.4c01304

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 mu M) 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.

引用

页码：15691 / 15710

页数：20