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

Iram Fatima, Jaya Prakash Uppada, Yashpal S. Chhonker, Saiprasad Gowrikumar, Susmita Barman, Sourav Roy, Kirsten T. Tolentino, Nicholas Palermo, Amar Natarajan, Daniel R. Beauchamp, Alex Vecchio, Daryl J. Murry, Amar B. Singh, Corey R. Hopkins, Punita Dhawan

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageEnglish (US)
Article number114255
JournalBiomedicine and Pharmacotherapy
Volume159
DOIs
StatePublished - Mar 2023

Keywords

  • Chemoresistance
  • Claudin-1
  • Colon cancer
  • Src

ASJC Scopus subject areas

  • Pharmacology

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