Benzyl and naphthalene methylphosphonic acid inhibitors of autotaxin with anti-invasive and anti-metastatic activity

Renuka Gupte, Renukadevi Patil, Jianxiong Liu, Yaohong Wang, Sue C. Lee, Yuko Fujiwara, James Fells, Alyssa L. Bolen, Karin Emmons-Thompson, C. Ryan Yates, Anjaih Siddam, Nattapon Panupinthu, Truc Chi T Pham, Daniel L. Baker, Abby L. Parrill, Gordon Mills, Gabor Tigyi, Duane D. Miller

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Autotaxin (ATX, NPP2) is a member of the nucleotide pyrophosphate phosphodiesterase enzyme family. ATX catalyzes the hydrolytic cleavage of lysophosphatidylcholine (LPC) by lysophospholipaseD activity, which leads to generation of the growth-factor-like lipid mediator lysophosphatidic acid (LPA). ATX is highly upregulated in metastatic and chemotherapy-resistant carcinomas and represents a potential target to mediate cancer invasion and metastasis. Herein we report the synthesis and pharmacological characterization of ATX inhibitors based on the 4-tetradecanoylaminobenzylphosphonic acid scaffold, which was previously found to lack sufficient stability in cellular systems. The new 4-substituted benzylphosphonic acid and 6-substituted naphthalen-2-ylmethylphosphonic acid analogues block ATX activity with Ki values in the low micromolar to nanomolar range against FS3, LPC, and nucleotide substrates through a mixed-mode inhibition mechanism. None of the compounds tested inhibit the activity of related enzymes (NPP6 and NPP7). In addition, the compounds were evaluated as agonists or antagonists of seven LPA receptor (LPAR) subtypes. Analogues 22 and 30b, the two most potent ATX inhibitors, inhibit the invasion of MM1 hepatoma cells across murine mesothelial and human vascular endothelial monolayers invitro in a dose-dependent manner. The average terminal half-life for compound 22 is 10±5.4h and it causes a long-lasting decrease in plasma LPA levels. Compounds 22 and 30b significantly decrease lung metastasis of B16-F10 syngeneic mouse melanoma in a post-inoculation treatment paradigm. The 4-substituted benzylphosphonic acids and 6-substituted naphthalen-2-ylmethylphosphonic acids described herein represent new lead compounds that effectively inhibit the ATX-LPA-LPAR axis both invitro and invivo. Inhibiting the ATX-LPA-LPAR axis: New 4-substituted benzylphosphonic acid and 6-substituted naphthalen-2-ylmethylphosphonic acid analogues were synthesized, and the most potent ATX inhibitors, 22 and 30b, show outstanding invivo profiles by diminishing lung metastases of B16-F10 syngeneic mouse melanoma in a post-inoculation treatment model. These two lead compounds effectively inhibit the ATX-LPA-LPAR axis both invitro and invivo.

Original languageEnglish (US)
Pages (from-to)922-935
Number of pages14
JournalChemMedChem
Volume6
Issue number5
DOIs
StatePublished - May 2 2011
Externally publishedYes

Fingerprint

Lysophosphatidic Acid Receptors
Lead compounds
Lysophosphatidylcholines
Acids
Nucleotides
Neoplasm Metastasis
Melanoma
Chemotherapy
Phosphoric Diester Hydrolases
Enzymes
Scaffolds
Lung
Monolayers
Intercellular Signaling Peptides and Proteins
naphthalene
methylphosphonic acid
lysophosphatidic acid
Lipids
Plasmas
Blood Vessels

Keywords

  • Inhibitors
  • Phosphonic acids
  • Receptors
  • Structure-activity relationships

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine

Cite this

Gupte, R., Patil, R., Liu, J., Wang, Y., Lee, S. C., Fujiwara, Y., ... Miller, D. D. (2011). Benzyl and naphthalene methylphosphonic acid inhibitors of autotaxin with anti-invasive and anti-metastatic activity. ChemMedChem, 6(5), 922-935. https://doi.org/10.1002/cmdc.201000425

Benzyl and naphthalene methylphosphonic acid inhibitors of autotaxin with anti-invasive and anti-metastatic activity. / Gupte, Renuka; Patil, Renukadevi; Liu, Jianxiong; Wang, Yaohong; Lee, Sue C.; Fujiwara, Yuko; Fells, James; Bolen, Alyssa L.; Emmons-Thompson, Karin; Yates, C. Ryan; Siddam, Anjaih; Panupinthu, Nattapon; Pham, Truc Chi T; Baker, Daniel L.; Parrill, Abby L.; Mills, Gordon; Tigyi, Gabor; Miller, Duane D.

In: ChemMedChem, Vol. 6, No. 5, 02.05.2011, p. 922-935.

Research output: Contribution to journalArticle

Gupte, R, Patil, R, Liu, J, Wang, Y, Lee, SC, Fujiwara, Y, Fells, J, Bolen, AL, Emmons-Thompson, K, Yates, CR, Siddam, A, Panupinthu, N, Pham, TCT, Baker, DL, Parrill, AL, Mills, G, Tigyi, G & Miller, DD 2011, 'Benzyl and naphthalene methylphosphonic acid inhibitors of autotaxin with anti-invasive and anti-metastatic activity', ChemMedChem, vol. 6, no. 5, pp. 922-935. https://doi.org/10.1002/cmdc.201000425
Gupte, Renuka ; Patil, Renukadevi ; Liu, Jianxiong ; Wang, Yaohong ; Lee, Sue C. ; Fujiwara, Yuko ; Fells, James ; Bolen, Alyssa L. ; Emmons-Thompson, Karin ; Yates, C. Ryan ; Siddam, Anjaih ; Panupinthu, Nattapon ; Pham, Truc Chi T ; Baker, Daniel L. ; Parrill, Abby L. ; Mills, Gordon ; Tigyi, Gabor ; Miller, Duane D. / Benzyl and naphthalene methylphosphonic acid inhibitors of autotaxin with anti-invasive and anti-metastatic activity. In: ChemMedChem. 2011 ; Vol. 6, No. 5. pp. 922-935.
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T1 - Benzyl and naphthalene methylphosphonic acid inhibitors of autotaxin with anti-invasive and anti-metastatic activity

AU - Gupte, Renuka

AU - Patil, Renukadevi

AU - Liu, Jianxiong

AU - Wang, Yaohong

AU - Lee, Sue C.

AU - Fujiwara, Yuko

AU - Fells, James

AU - Bolen, Alyssa L.

AU - Emmons-Thompson, Karin

AU - Yates, C. Ryan

AU - Siddam, Anjaih

AU - Panupinthu, Nattapon

AU - Pham, Truc Chi T

AU - Baker, Daniel L.

AU - Parrill, Abby L.

AU - Mills, Gordon

AU - Tigyi, Gabor

AU - Miller, Duane D.

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KW - Inhibitors

KW - Phosphonic acids

KW - Receptors

KW - Structure-activity relationships

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