title: Vinyl sulfone analogs of lysophosphatidylcholine irreversibly inhibit autotaxin and prevent angiogenesis in melanoma.
abstract: Autotaxin (ATX) is an enzyme discovered in the conditioned medium of cultured melanoma cells and identified as a protein that strongly stimulates motility. This unique ectonucleotide pyrophosphatase and phosphodiesterase facilitates the removal of a choline headgroup from lysophosphatidylcholine (LPC) to yield lysophosphatidic acid (LPA), which is a potent lipid stimulator of tumorigenesis. Thus, ATX has received renewed attention because it has a prominent role in malignant progression with significant translational potential. Specifically, we sought to develop active site-targeted irreversible inhibitors as anti-cancer agents. Herein we describe the synthesis and biological activity of an LPC-mimetic electrophilic affinity label that targets the active site of ATX, which has a critical threonine residue that acts as a nucleophile in the lysophospholipase D reaction to liberate choline. We synthesized a set of quaternary ammonium derivative-containing vinyl sulfone analogs of LPC that function as irreversible inhibitors of ATX and inactivate the enzyme. The analogs were tested in cell viability assays using multiple cancer cell lines. The IC50 values ranged from 6.74 to 0.39 μM, consistent with a Ki of 3.50 μM for inhibition of ATX by the C16H33 vinyl sulfone analog CVS-16 (10b). A phenyl vinyl sulfone control compound, PVS-16, lacking the choline-like quaternary ammonium mimicking head group moiety, had little effect on cell viability and did not inhibit ATX. Most importantly, CVS-16 (10b) significantly inhibited melanoma progression in an in vivo tumor model by preventing angiogenesis. Taken together, this suggests that CVS-16 (10b) is a potent and irreversible ATX inhibitor with significant biological activity both in vitro and in vivo.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, College of Pharmacy, 240 W. Green Street, Athens, GA 30602, United States. Electronic address: mmurph@uga.edu.
authors.forename: Mandi M
authors.initials: MM
authors.lastname: Murph
authors.affiliation: Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, UT 84108-1257, United States.
authors.forename: Guowei W
authors.initials: GW
authors.lastname: Jiang
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, College of Pharmacy, 240 W. Green Street, Athens, GA 30602, United States.
authors.forename: Molly K
authors.initials: MK
authors.lastname: Altman
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, College of Pharmacy, 240 W. Green Street, Athens, GA 30602, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Jia
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, College of Pharmacy, 240 W. Green Street, Athens, GA 30602, United States.
authors.forename: Duy T
authors.initials: DT
authors.lastname: Nguyen
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, College of Pharmacy, 240 W. Green Street, Athens, GA 30602, United States.
authors.forename: Jada M
authors.initials: JM
authors.lastname: Fambrough
authors.affiliation: The University of Georgia and Georgia Regents University Medical Partnership, 1425 Prince Avenue, Athens, GA 30606, United States.
authors.forename: William J
authors.initials: WJ
authors.lastname: Hardman
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, College of Pharmacy, 240 W. Green Street, Athens, GA 30602, United States.
authors.forename: Ha T
authors.initials: HT
authors.lastname: Nguyen
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, College of Pharmacy, 240 W. Green Street, Athens, GA 30602, United States.
authors.forename: Sterling K
authors.initials: SK
authors.lastname: Tran
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, College of Pharmacy, 240 W. Green Street, Athens, GA 30602, United States.
authors.forename: Ali A
authors.initials: AA
authors.lastname: Alshamrani
authors.affiliation: Echelon Biosciences Incorporated, 675 Arapeen Way, Suite 302, Salt Lake City, UT 84108, United States.
authors.forename: Damian
authors.initials: D
authors.lastname: Madan
authors.affiliation: Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, UT 84108-1257, United States.
authors.forename: Jianxing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, UT 84108-1257, United States. Electronic address: gprestwich@pharm.utah.edu.
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Prestwich
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D008244:Lysophosphatidylcholines / Q000008:administration & dosage / Q000627:therapeutic use*; D008545:Melanoma / Q000188:drug therapy*; D009389:Neovascularization, Pathologic; D013450:Sulfones / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D008244:Lysophosphatidylcholines; D013450:Sulfones; C512310:phenyl vinyl sulfone
keywords: Angiogenesis; Anticancer therapy; Autotaxin; Lysophosphatidylcholine; Melanoma; Vinyl sulfone