GSK-3α inhibitors(University of Central Lancashire)(GSK-3α inhibitors(University of Central Lancashire)) - 药物靶点：GSK-3α_在研适应症：胶质母细胞瘤_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Compound 1(University of Central Lancashire)

靶点

GSK-3α

作用方式

抑制剂

作用机制

GSK-3α抑制剂(glycogen synthase kinase 3 alpha inhibitors)

治疗领域

肿瘤神经系统疾病其他疾病

在研适应症

胶质母细胞瘤

非在研适应症-

原研机构

University of Central Lancashire

在研机构

University of Central Lancashire

非在研机构-

权益机构-

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

关联

100 项与 GSK-3α inhibitors(University of Central Lancashire) 相关的临床结果

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100 项与 GSK-3α inhibitors(University of Central Lancashire) 相关的转化医学

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100 项与 GSK-3α inhibitors(University of Central Lancashire) 相关的专利（医药）

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1

项与 GSK-3α inhibitors(University of Central Lancashire) 相关的文献（医药）

2025-04-24·Journal of Medicinal Chemistry

Structure-Based Discovery Targeting GSK-3α Reveals Potent Nanomolar Selective 4-Phenyl-1H-benzofuro[3,2-b]pyrazolo[4,3-e]pyridine Inhibitor with Promising Glioblastoma and CNS-Active Potential in Cellular Models

Article

作者: Martinez-Gonzalez, Loreto ; Berenschot, Erwin ; Dickens, Kathryn ; Alder, Jane ; Emmerich, Thomas D. ; Martinez, Ana ; Stasik, Izabela ; Hayes, Joseph M. ; Oknianska, Alina ; Taylor-Chilton, Eleanor J. ; Hushcha, Iryna ; Zwain, Tamara ; Susarrey-Arce, Arturo ; Tas, Niels R. ; Caballero, Elena ; Saavedra-Castano, Santiago

Glycogen synthase kinase-3 (GSK-3) is linked with multiple CNS conditions, including glioblastoma (GBM). Compared to the GSK-3β isoform, structure-based inhibitor design targeting GSK-3α is limited. Virtual screening was employed to identify GSK-3α inhibitors with CNS-active potential. Using a GSK-3α homology model, an optimized protocol with three-dimensional (3D)-pharmacophore filtering and Glide-SP docking was used to screen the ZINC20 biogenic subset. From 14 compounds selected for binding assay validation, three novel hit compounds were identified, with 1 (4-phenyl-1H-benzofuro[3,2-b]pyrazolo[4,3-e]pyridine scaffold) exhibiting nanomolar activity against GSK-3α/β (IC₅₀s ∼ 0.26 μM). Selectivity profiling (12 homologous kinases) revealed selectivity for GSK-3α/β and protein kinase A (PKA). Compound 1 was more potent against three GBM cell lines (cell viability IC₅₀s = 3-6 μM at 72 h) compared to benchmark GSK-3 inhibitor, 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8), and nontoxic to human astrocytes. It demonstrated CNS-active potential in an all-human in vitro blood-brain barrier GBM model, good in vitro metabolic stability, excellent predicted oral bioavailability and represents a promising lead compound for development.

100 项与 GSK-3α inhibitors(University of Central Lancashire) 相关的药物交易

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