The tumor-enriched small molecule gambogic amide suppresses glioma by targeting WDR1-dependent cytoskeleton remodeling
Jiaorong Qu # 1 2, Bojun Qiu # 1 2, Yuxin
Zhang 1 2, Yan Hu 1 2, Zhixing Wang 1 2, Zhiang Guan 1 2, Yiming Qin 1 2,
Tongtong Sui 1 2, Fan Wu 3 4, Boyang Li 1 2, Wei Han 5 6, Xiaozhong Peng 7 8 9
Signal Transduct Target Ther.2023 Nov
8;8(1):424. doi: 10.1038/s41392-023-01666-3.
PMID: 37935665
Abstract
Glioma is the most prevalent brain tumor,
presenting with limited treatment options, while patients with malignant glioma
and glioblastoma (GBM) have poor prognoses. The physical obstacle to drug
delivery imposed by the blood?brain barrier (BBB) and glioma stem cells (GSCs),
which are widely recognized as crucial elements contributing to the
unsatisfactory clinical outcomes. In this study, we found a small molecule,
gambogic amide (GA-amide), exhibited the ability to effectively penetrate the
blood-brain barrier (BBB) and displayed a notable enrichment within the tumor
region. Moreover, GA-amide exhibited significant efficacy in inhibiting tumor
growth across various in vivo glioma models, encompassing transgenic and
primary patient-derived xenograft (PDX) models. We further performed a
genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)
knockout screen to determine the druggable target of GA-amide. By the
combination of the cellular thermal shift assay (CETSA), the drug affinity
responsive target stability (DARTS) approach, molecular docking simulation and
surface plasmon resonance (SPR) analysis, WD repeat domain 1 (WDR1) was
identified as the direct binding target of GA-amide. Through direct interaction
with WDR1, GA-amide promoted the formation of a complex involving WDR1, MYH9
and Cofilin, which accelerate the depolymerization of F-actin to inhibit the
invasion of patient-derived glioma cells (PDCs) and induce PDC apoptosis via
the mitochondrial apoptotic pathway. In conclusion, our study not only
identified GA-amide as an effective and safe agent for treating glioma but also
shed light on the underlying mechanisms of GA-amide from the perspective of
cytoskeletal homeostasis.