Identification and characterization of a first-generation inhibitor of claudin-1 in colon cancer progression and metastasis - 03/02/23
Abstract |
Colorectal cancer (CRC) is a leading cause of the cancer-related deaths worldwide. Thus, developing novel and targeted therapies for inhibiting CRC progression and metastasis is urgent. Several studies, including ours, have reported a causal role for an upregulated claudin-1 expression in promoting CRC metastasis through the activation of the Src and β-catenin-signaling. In murine models of colon tumorigenesis, claudin-1 overexpression promotes oncogenic properties such as transformation and invasiveness. Conversely, the downregulation of claudin-1 inhibits colon tumorigenesis. Despite being a desirable target for cancer treatment, there are currently no known claudin-1 inhibitors with antitumor efficacy. Using a rigorous analytical design and implementing in- vitro and in-vivo testing and a brief medicinal chemistry campaign, we identified a claudin-1-specific inhibitor and named it I-6. Despite its high potency, I-6 was rapidly cleared in human liver microsomes. We, therefore, synthesized I-6 analogs and discovered a novel small molecule, PDS-0330. We determined that PDS0330 inhibits claudin-1-dependent CRC progression without exhibiting toxicity in in-vitro and in-vivo models of CRC and that it binds directly and specifically to claudin-1 with micromolar affinity. Further analyses revealed that PDS-0330 exhibits antitumor and chemosensitizer activities with favorable pharmacokinetic properties by inhibiting the association with metastatic oncogene Src. Overall, our data propose that PDS-0330 interferes with claudin-1/Src association to inhibit CRC progression and metastasis. Our findings are of direct clinical relevance and may open new therapeutic opportunities in colon cancer treatment and/or management by targeting claudin-1.
Le texte complet de cet article est disponible en PDF.Highlights |
• | This study focuses on preclinical testing for a new claudin-1 inhibitor PDS0330 in Colorectal Cancer. |
• | PDS0330 inhibits claudin-1-dependent CRC progression. |
• | PDS-0330 selectively binds to claudin-1 and inhibits the Src association. |
• | PDS-0330 suppresses anoikis resistance, reduces invasion and enhances apoptosis. |
Keywords : Claudin-1, Colon cancer, Src, Chemoresistance
Plan
Vol 159
Article 114255- mars 2023 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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