Vinyl sulfone analogs of lysophosphatidylcholine irreversibly inhibit autotaxin and prevent angiogenesis in melanoma

Mandi M. Murph, Guowei W. Jiang, Molly K. Altman, Wei Jia, Duy T. Nguyen, Jada M. Fambrough, William Jackson Hardman, Ha T. Nguyen, Sterling K. Tran, Ali A. Alshamrani, Damian Madan, Jianxing Zhang, Glenn D. Prestwich

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)5999-6013
Number of pages15
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number17
DOIs
StatePublished - Mar 31 2015

Fingerprint

Lysophosphatidylcholines
Choline
Melanoma
Cells
Bioactivity
Ammonium Compounds
Catalytic Domain
Cell Survival
Affinity Labels
Pyrophosphatases
Neoplasms
Nucleophiles
Phosphoric Diester Hydrolases
Enzymes
Threonine
Conditioned Culture Medium
Inhibitory Concentration 50
Tumors
Cultured Cells
Assays

Keywords

  • Angiogenesis
  • Anticancer therapy
  • Autotaxin
  • Lysophosphatidylcholine
  • Melanoma
  • Vinyl sulfone

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Murph, M. M., Jiang, G. W., Altman, M. K., Jia, W., Nguyen, D. T., Fambrough, J. M., ... Prestwich, G. D. (2015). Vinyl sulfone analogs of lysophosphatidylcholine irreversibly inhibit autotaxin and prevent angiogenesis in melanoma. Bioorganic and Medicinal Chemistry, 23(17), 5999-6013. https://doi.org/10.1016/j.bmc.2015.06.054

Vinyl sulfone analogs of lysophosphatidylcholine irreversibly inhibit autotaxin and prevent angiogenesis in melanoma. / Murph, Mandi M.; Jiang, Guowei W.; Altman, Molly K.; Jia, Wei; Nguyen, Duy T.; Fambrough, Jada M.; Hardman, William Jackson; Nguyen, Ha T.; Tran, Sterling K.; Alshamrani, Ali A.; Madan, Damian; Zhang, Jianxing; Prestwich, Glenn D.

In: Bioorganic and Medicinal Chemistry, Vol. 23, No. 17, 31.03.2015, p. 5999-6013.

Research output: Contribution to journalArticle

Murph, MM, Jiang, GW, Altman, MK, Jia, W, Nguyen, DT, Fambrough, JM, Hardman, WJ, Nguyen, HT, Tran, SK, Alshamrani, AA, Madan, D, Zhang, J & Prestwich, GD 2015, 'Vinyl sulfone analogs of lysophosphatidylcholine irreversibly inhibit autotaxin and prevent angiogenesis in melanoma', Bioorganic and Medicinal Chemistry, vol. 23, no. 17, pp. 5999-6013. https://doi.org/10.1016/j.bmc.2015.06.054
Murph, Mandi M. ; Jiang, Guowei W. ; Altman, Molly K. ; Jia, Wei ; Nguyen, Duy T. ; Fambrough, Jada M. ; Hardman, William Jackson ; Nguyen, Ha T. ; Tran, Sterling K. ; Alshamrani, Ali A. ; Madan, Damian ; Zhang, Jianxing ; Prestwich, Glenn D. / Vinyl sulfone analogs of lysophosphatidylcholine irreversibly inhibit autotaxin and prevent angiogenesis in melanoma. In: Bioorganic and Medicinal Chemistry. 2015 ; Vol. 23, No. 17. pp. 5999-6013.
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AU - Jia, Wei

AU - Nguyen, Duy T.

AU - Fambrough, Jada M.

AU - Hardman, William Jackson

AU - Nguyen, Ha T.

AU - Tran, Sterling K.

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