3053 - Small Molecule G07 Exhibits Dual Effects on Cell Motility by Enhancing Skin Wound Healing and Inhibiting Nasopharyngeal Carcinoma Metastasis
Presenter(s)
L. Guo1,2, T. Wang1, and C. N. Qian2,3; 1Peking University Shenzhen Hospital, Shenzhen, Guangdong, China, 2Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China, 3Guangzhou Concord Cancer Center, Guangzhou, Guangdong, China
Purpose/Objective(s): The global burden of diabetes mellitus and malignancy has escalated markedly in recent decades, positioning impaired wound repair and cancer metastasis as critical clinical challenges. Current therapeutic strategies remain limited in addressing these pathophysiological dichotomies-hypoactive fibroblast motility in chronic diabetic wounds versus hyperactivated tumor cell dissemination. This bidirectional dysregulation of cellular migration underscores the pressing need for pharmacological agents capable of context-dependent modulation. We hypothesized that dual-function small molecules could differentially regulate cell motility-enhancing tissue repair while suppressing cancer metastasis.
Materials/Methods: A high-throughput screening platform targeting cytoskeleton-associated proteins was used to identify small-molecule compounds with bidirectional motility modulation capacity. Functional validation through scratch wound assays, Transwell migration, and Matrigel invasion assays demonstrated differential effects on fibroblast versus nasopharyngeal carcinoma (NPC) cell motility. Therapeutic efficacy was evaluated in streptozotocin-induced diabetic murine wound models, the subcutaneous xenograft models and lung metastasis models of NPC. Target engagement was confirmed via pull-down assays coupled with LC-MS/MS proteomics, followed by molecular docking simulation. CRISPR-Cas9-mediated knockdown of candidate targets in fibroblasts abolished compound-induced pro-migratory effects.
Results: High-content phenotypic screening identified 5-(isobutoxymethyl)-8-quinolinol hydrochloride (G07) as a bifunctional motility regulator. Pharmacodynamic profiling demonstrated G07's capacity to accelerate fibroblast migration and collagen deposition in diabetic murine wounds, while suppressing NPC metastasis in subcutaneous xenograft models and lung metastasis models. Target deconvolution via chemoproteomics revealed selective engagement with the Actin-Related Protein 2/3 (ARP2/3) complex, corroborated by molecular docking. Both G07 treatment and CRISPR-Cas9-mediated ARP2/3 knockdown enhanced fibroblast motility, whereas ARP2/3-deficient cells exhibited complete abrogation of G07's pro-migratory effect, indicating shared migratory modulation pathways.
Conclusion: Our study identifies and validates the small-molecule agent G07, which accelerates wound closure and selectively suppresses NPC metastasis. Through systematic characterization, we demonstrate that ARP2/3 serves as a critical mediator of G07's dual regulatory effects on cellular motility. Specifically, G07 exerts stimulatory effects in normal fibroblasts while inhibiting malignant cell migration through modulating ARP2/3 activity. This work establishes a molecular framework for understanding G07's therapeutic potential and provides insights into developing targeted therapies for wound repair and cancer metastasis.