ArticleMolecular cancer2026
An orally bioavailable pan-αv/α5β1 integrin antagonist prevents aggressive prostate cancer progression via suppressing both oncogenic signals and CD47-mediated immune escape.
Article in Molecular cancer, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundAdvanced prostate cancer (PCa), particularly enzalutamide-resistant, bone-metastatic castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC), remains an intractable clinical challenge due to oncogenic crosstalk across multiple pathways and tumor microenvironment (TME) heterogeneity. Given these unmet clinical needs, novel targeted therapeutics are urgently required to improve advanced PCa patient outcomes.
methodsIn this study, we examined the expression of integrin subtypes, particularly pan-αv integrins and α5β1, in prostate cancertumor samples and cell lines using immunohistochemistry (IHC) and Western blotting. Based on rational drug design, we synthesized a first-in-class, orally bioavailable, non-RGD pan-αv/α5β1 integrin antagonist, C19-9N, and characterized it through homology modeling, molecular docking, surface plasmon resonance (SPR), and microscale thermophoresis (MST). The antitumor activity of C19-9N was evaluated in vitro (via assays of cell viability, migration and invasion) and in vivo using multiple models, including subcutaneous xenografts of CRPC, bone-metastatic xenograft models established by intratibial and intracardiac injection, and patient-derived xenografts (PDXs) of NEPC. The in vivo safety and pharmacokinetic profile of C19-9N were also assessed. Mechanistically, single-cell RNA sequencing (scRNA-seq) was employed to uncover the regulatory effects of C19-9N on infiltrating immune cells within the tumor microenvironment, which were further validated through multiplex immunofluorescence and bone marrow-derived macrophage-mediated phagocytosis assays.
resultsC19-9N targeting pan-αv and α5β1 integrin circumvented potential compensatory resistance mediated by integrin subtype switching. C19-9N disrupted extracellular matrix (ECM)-integrin biochemical and mechanical signaling, thereby suppressing cancer stem cell (CSC) self-renewal and epithelial-to-mesenchymal transition (EMT). Mechanistically, C19-9N inhibited PI3K/AKT and STAT3 signaling pathways to block alternative splicing of AR-V7, and modulated Survivin and c-Myc to enhance enzalutamide sensitivity. Additionally, it remodeled TME by repolarizing tumor-associated macrophages (TAMs) toward a pro-inflammatory phenotype and downregulating CD47-mediated immune escape. In preclinical models, C19-9N overcame enzalutamide resistance in CRPC xenografts, suppressed bone metastatic progression, and exhibited superior efficacy to platinum/taxane therapies in NEPC.
conclusionCollectively, by co-targeting oncogenic drivers and TME vulnerabilities, C19-9N heralds a transformative therapeutic paradigm with profound clinical potential for aggressive PCa.
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