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Research ArticleDrug Discovery and Translational Medicine

Selective Inhibition of Autotaxin Is Efficacious in Mouse Models of Liver Fibrosis

Gretchen Bain, Kristen E. Shannon, Fei Huang, Janice Darlington, Lance Goulet, Patricia Prodanovich, Gina L. Ma, Angelina M. Santini, Adam J. Stein, Dave Lonergan, Christopher D. King, Imelda Calderon, Andiliy Lai, John H. Hutchinson and Jilly F. Evans
Journal of Pharmacology and Experimental Therapeutics January 2017, 360 (1) 1-13; DOI: https://doi.org/10.1124/jpet.116.237156
Gretchen Bain
PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
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Kristen E. Shannon
PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
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Fei Huang
PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
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Janice Darlington
PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
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Lance Goulet
PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
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Patricia Prodanovich
PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
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Gina L. Ma
PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
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Angelina M. Santini
PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
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Adam J. Stein
PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
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Dave Lonergan
PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
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Christopher D. King
PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
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Imelda Calderon
PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
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Andiliy Lai
PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
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John H. Hutchinson
PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
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Jilly F. Evans
PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
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Abstract

Autotaxin (ATX) is a secreted glycoprotein that converts lysophosphatidylcholine (LPC) to the bioactive phospholipid lysophosphatidic acid (LPA) and is the major enzyme generating circulating LPA. Inhibition of LPA signaling has profound antifibrotic effects in multiple organ systems, including lung, kidney, skin, and peritoneum. However, other LPA-generating pathways exist, and the role of ATX in localized tissue LPA production and fibrosis remains unclear and controversial. In this study, we describe the preclinical pharmacologic, pharmacokinetic, and pharmacodynamic properties of a novel small-molecule ATX inhibitor, PAT-505 [3-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl) thio)-2-fluorobenzoic acid sodium salt]. PAT-505 is a potent, selective, noncompetitive inhibitor that displays significant inhibition of ATX activity in plasma and liver tissue after oral administration. When dosed therapeutically in a Stelic Mouse Animal Model of nonalcoholic steatohepatitis (NASH), PAT-505 treatment resulted in a small but significant improvement in fibrosis with only minor improvements in hepatocellular ballooning and hepatic inflammation. In a choline-deficient, high-fat diet model of NASH, therapeutic treatment with PAT-505 robustly reduced liver fibrosis with no significant effect on steatosis, hepatocellular ballooning, or inflammation. These data demonstrate that inhibiting autotaxin is antifibrotic and may represent a novel therapeutic approach for the treatment of multiple fibrotic liver diseases, including NASH.

Footnotes

    • Received August 9, 2016.
    • Accepted October 14, 2016.
  • dx.doi.org/10.1124/jpet.116.237156.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 360 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 360, Issue 1
1 Jan 2017
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Research ArticleDrug Discovery and Translational Medicine

Autotaxin Inhibition Attenuates Mouse Liver Fibrosis

Gretchen Bain, Kristen E. Shannon, Fei Huang, Janice Darlington, Lance Goulet, Patricia Prodanovich, Gina L. Ma, Angelina M. Santini, Adam J. Stein, Dave Lonergan, Christopher D. King, Imelda Calderon, Andiliy Lai, John H. Hutchinson and Jilly F. Evans
Journal of Pharmacology and Experimental Therapeutics January 1, 2017, 360 (1) 1-13; DOI: https://doi.org/10.1124/jpet.116.237156

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Research ArticleDrug Discovery and Translational Medicine

Autotaxin Inhibition Attenuates Mouse Liver Fibrosis

Gretchen Bain, Kristen E. Shannon, Fei Huang, Janice Darlington, Lance Goulet, Patricia Prodanovich, Gina L. Ma, Angelina M. Santini, Adam J. Stein, Dave Lonergan, Christopher D. King, Imelda Calderon, Andiliy Lai, John H. Hutchinson and Jilly F. Evans
Journal of Pharmacology and Experimental Therapeutics January 1, 2017, 360 (1) 1-13; DOI: https://doi.org/10.1124/jpet.116.237156
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