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.
Clinical treatment of temozolomide (TMZ)-resistant glioblastoma (GBM) remains a significant challenge. This study aims to develop a multifunctional biomimetic Nano-AUTAC (BM@pPPD/TMZ) that can selectively degrade β-catenin via autophagy, thereby overcoming TMZ resistance in GBM. BM@pPPD/TMZ is capable of penetrating the blood-brain barrier (BBB), targeting GBM lesions via microglia-derived membrane camouflage, and inducing degradation of β-catenin through the autophagy-lysosomal pathway. For improving the selective and efficient degradation of β-catenin, BM@pPPD/TMZ is functionalized with a tri-functional peptide comprising a β-catenin-binding domain, a cathepsin B (CTSB)-cleavable GLFG linker, and a phosphatidylserine (PS)-targeting motif. In the GBM microenvironment, the elevated CTSB triggers linker cleavage, promoting membrane shedding and enhancing the cellular uptake. Meanwhile, the incorporation of the cationic lipid DOTAP promotes autophagosome formation, further facilitating degradation of β-catenin. Both in vitro and in vivo studies demonstrate that BM@pPPD/TMZ is able to effectively penetrate the BBB and accumulate within tumor lesion, concurrently promoting β-catenin degradation and MGMT downregulation. This finding provides a promising nanotherapeutic strategy for overcoming TMZ resistance and improving GBM therapeutic efficacy.
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