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

Erica N Parker; Samuel O Odutola; Yifan Wang; Tracy E Strecker; Rajeswari Mukherjee; Zhe Shi; David J Chaplin; Mary Lynn Trawick; Kevin G Pinney

doi:10.1016/j.bmcl.2016.12.039

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. Epub 2016 Dec 21.

Authors

Erica N Parker¹, Samuel O Odutola², Yifan Wang¹, Tracy E Strecker¹, Rajeswari Mukherjee¹, Zhe Shi¹, David J Chaplin³, Mary Lynn Trawick⁴, Kevin G Pinney⁵

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: [email protected].
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: [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Cathepsin L / antagonists & inhibitors*
Cell Line, Tumor
Enzyme Activation / drug effects
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Humans
Molecular Structure
Organophosphates / chemistry*
Prodrugs / chemical synthesis*
Prodrugs / chemistry
Prodrugs / pharmacology*
Salts / chemical synthesis
Salts / pharmacology
Solubility
Thiosemicarbazones / chemical synthesis*
Thiosemicarbazones / chemistry
Thiosemicarbazones / pharmacology*
Thiourea / analogs & derivatives*
Thiourea / chemical synthesis
Thiourea / chemistry
Thiourea / pharmacology
Water / chemistry

Substances

Antineoplastic Agents
Enzyme Inhibitors
KGP94
KPG420
Organophosphates
Prodrugs
Salts
Thiosemicarbazones
Water
Cathepsin L
Thiourea