1. Academic Validation
  2. ASR490, a Small Molecule, Overrides Aberrant Expression of Notch1 in Colorectal Cancer

ASR490, a Small Molecule, Overrides Aberrant Expression of Notch1 in Colorectal Cancer

  • Mol Cancer Ther. 2020 Dec;19(12):2422-2431. doi: 10.1158/1535-7163.MCT-19-0949.
Ashish Tyagi 1 Balaji Chandrasekaran 1 Venkatesh Kolluru 1 Becca V Baby 1 Cibi A Sripathi 1 Murali K Ankem 1 Srinivasa R Ramisetti 2 Venkat R Chirasani 2 Nikolay V Dokholyan 3 Arun K Sharma 2 Chendil Damodaran 4
Affiliations

Affiliations

  • 1 Department of Urology, University of Louisville, Louisville, Kentucky.
  • 2 Department of Pharmacology, Penn State Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania.
  • 3 Department of Pharmacology, Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, Pennsylvania.
  • 4 Department of Urology, University of Louisville, Louisville, Kentucky. chendil.damodaran@louisville.edu.
Abstract

Notch1 activation triggers significant oncogenic signaling that manifests as enhanced metastatic potential and tumorigenesis in colorectal Cancer. Novel small-molecule inhibitors, mainly plant-derived analogs, have low toxicity profiles and higher bioavailability. In this study, we have developed a small molecule, ASR490, by modifying structure of naturally occurring compound Withaferin A. ASR490 showed a growth-inhibitory potential by downregulating Notch1 signaling in HCT116 and SW620 cell lines. Docking studies and thermal shift assays confirmed that ASR490 binds to Notch1, whereas no changes in Notch2 and Notch3 expression were seen in colorectal Cancer cells. Notch1 governs epithelial-to-mesenchymal transition signaling and is responsible for metastasis, which was abolished by ASR490 treatment. To further confirm the therapeutic potential of ASR490, we stably overexpressed Notch1 in HCT-116 cells and determined its inhibitory potential in transfected colorectal Cancer (Notch1/HCT116) cells. ASR490 effectively prevented cell growth in both the vector (P = 0.005) and Notch1 (P = 0.05) transfectants. The downregulation of Notch1 signaling was evident, which corresponded with downregulation of mesenchymal markers, including N-Cadherin and β-catenin and induction of E-cadherin in HCT-116 transfectants. Intraperitoneal administration of a 1% MTD dose of ASR490 (5 mg/kg) effectively suppressed the tumor growth in control (pCMV/HCT116) and Notch1/HCT116 in xenotransplanted mice. In addition, downregulation of Notch1 and survival signaling in ASR-treated tumors confirmed the in vitro results. In conclusion, ASR490 appears to be a potent agent that can inhibit Notch1 signaling in colorectal Cancer.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-144899
    99.05%, Notch1 Inhibitor