title: Synthesis and biological evaluation of a water-soluble phosphate prodrug salt and structural analogues of KGP94, a lead inhibitor of cathepsin L.
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 IC50value 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.
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, United States.
authors.forename: Erica N
authors.initials: EN
authors.lastname: Parker
authors.affiliation: Institute of Biomedical Studies, Baylor University, One Bear Place #97224, Waco, TX 76798-7224, United States.
authors.forename: Samuel O
authors.initials: SO
authors.lastname: Odutola
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, United States.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, United States.
authors.forename: Tracy E
authors.initials: TE
authors.lastname: Strecker
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, United States.
authors.forename: Rajeswari
authors.initials: R
authors.lastname: Mukherjee
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, United States.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Shi
authors.affiliation: 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.
authors.forename: David J
authors.initials: DJ
authors.lastname: Chaplin
authors.affiliation: 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.
authors.forename: Mary Lynn
authors.initials: ML
authors.lastname: Trawick
authors.affiliation: 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.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Pinney
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D056668:Cathepsin L / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D010755:Organophosphates / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012492:Salts / Q000138:chemical synthesis / Q000494:pharmacology; D012995:Solubility; D013882:Thiosemicarbazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014867:Water / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C581086:KGP94; C000623115:KPG420; D010755:Organophosphates; D011355:Prodrugs; D012492:Salts; D013882:Thiosemicarbazones; D014867:Water; D056668:Cathepsin L; D013890:Thiourea
keywords: Anti-metastatic agent; Benzophenone; Cysteine protease inhibitor; Phosphate prodrug; Thiosemicarbazone