Identification and characterization of a first-generation inhibitor of claudin-1 in colon cancer progression and metastasis

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...

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Veröffentlicht in:Biomedicine & pharmacotherapy 2023-03, Vol.159, p.114255-114255, Article 114255
Hauptverfasser: Fatima, Iram, Uppada, Jaya Prakash, Chhonker, Yashpal S., Gowrikumar, Saiprasad, Barman, Susmita, Roy, Sourav, Tolentino, Kirsten T., Palermo, Nicholas, Natarajan, Amar, Beauchamp, Daniel R., Vecchio, Alex, Murry, Daryl J., Singh, Amar B., Hopkins, Corey R., Dhawan, Punita
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Sprache:eng
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Zusammenfassung: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. •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.
ISSN:0753-3322
1950-6007
1950-6007
DOI:10.1016/j.biopha.2023.114255