2. Academic Validation
  3. Synthesis and biological evaluation of a water-soluble phosphate prodrug salt and structural analogues of KGP94, a lead inhibitor of cathepsin L

Synthesis and biological evaluation of a water-soluble phosphate prodrug salt and structural analogues of KGP94, a lead inhibitor of cathepsin L

  • Bioorg Med Chem Lett. 2017 Mar 1;27(5):1304-1310. doi: 10.1016/j.bmcl.2016.12.039.
Erica N Parker 1,  Samuel O Odutola 2,  Yifan Wang 1,  Tracy E Strecker 1,  Rajeswari Mukherjee 1,  Zhe Shi 1,  David J Chaplin 3,  Mary Lynn Trawick 4,  Kevin G Pinney 5
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, United States.
  • 2 Institute of Biomedical Studies, Baylor University, One Bear Place #97224, Waco, TX 76798-7224, United States.
  • 3 Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, United States; Mateon Therapeutics, Inc., 701 Gateway Blvd, Suite 210, South San Francisco, CA 94080, United States.
  • 4 Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, United States; Institute of Biomedical Studies, Baylor University, One Bear Place #97224, Waco, TX 76798-7224, United States; Mateon Therapeutics, Inc., 701 Gateway Blvd, Suite 210, South San Francisco, CA 94080, United States. Electronic address: Mary_Lynn_Trawick@baylor.edu.
  • 5 Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, United States; Institute of Biomedical Studies, Baylor University, One Bear Place #97224, Waco, TX 76798-7224, United States; Mateon Therapeutics, Inc., 701 Gateway Blvd, Suite 210, South San Francisco, CA 94080, United States. Electronic address: Kevin_Pinney@baylor.edu.
PMID: 28117205 DOI: 10.1016/j.bmcl.2016.12.039
Abstract

The magnitude of expression of Cathepsin L, often upregulated in the tumor microenvironment, correlates with the invasive and metastatic nature of certain tumors. Inhibition of Cathepsin L represents an emerging strategy for the treatment of metastatic Cancer. A potent, small-molecule inhibitor (referred to as KGP94) of Cathepsin L, and new KGP94 analogues were synthesized. (3,5-Dibromophenyl)-(3-hydroxyphenyl) ketone thiosemicarbazone (22), with an IC50 value of 202nM, exhibited similar inhibitory activity against Cathepsin L compared to KGP94 (IC50=189nM). Due to limited aqueous solubility of KGP94, a water-soluble phosphate salt (KGP420) was prepared in order to facilitate future in vivo studies. Enzymatic hydrolysis with Alkaline Phosphatase (ALP) demonstrated that the phosphate prodrug, KGP420, was readily converted to the parent compound, KGP94.

Keywords

Anti-metastatic agent; Benzophenone; Cysteine protease inhibitor; Phosphate prodrug; Thiosemicarbazone.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-118762
    99.53%, Cathepsin L Inhibitor