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

  • Biomed Pharmacother. 2023 Mar;159:114255. doi: 10.1016/j.biopha.2023.114255.
Iram Fatima  1 ,  Jaya Prakash Uppada  1 ,  Yashpal S Chhonker  2 ,  Saiprasad Gowrikumar  1 ,  Susmita Barman  1 ,  Sourav Roy  3 ,  Kirsten T Tolentino  4 ,  Nicholas Palermo  5 ,  Amar Natarajan  6 ,  Daniel R Beauchamp  7 ,  Alex Vecchio  3 ,  Daryl J Murry  8 ,  Amar B Singh  9 ,  Corey R Hopkins  4 ,  Punita Dhawan  10
Affiliations
  • 1. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
  • 2. Department of Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, NE, USA.
  • 3. Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE 68588-0664, USA.
  • 4. Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
  • 5. Computational Chemistry Core, University of Nebraska Medical Center, Omaha, NE, USA.
  • 6. Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE, USA.
  • 7. Surgical Oncology Research Laboratories, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 8. Department of Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, NE, USA; VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA.
  • 9. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA; Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
  • 10. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA; Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. Electronic address: [email protected].
PMID: 36696800 DOI: 10.1016/j.biopha.2023.114255
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.

Keywords
Chemoresistance; Claudin-1; Colon cancer; Src.
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