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ACS medicinal chemistry letters
Jun 11, 2020;11 (6): 1335-1341.

ONO-8430506: A Novel Autotaxin Inhibitor That Enhances the Antitumor Effect of Paclitaxel in a Breast Cancer Model.

Yuzo Iwaki, Akira Ohhata, Shingo Nakatani, Katsuya Hisaichi, Yasuyuki Okabe, Atsushi Hiramatsu, Toshihide Watanabe, Shingo Yamamoto, Taihei Nishiyama, Juta Kobayashi, Yasuo Hirooka, Hideki Moriguchi, Tatsuo Maeda, Makoto Katoh, Yuka Komichi, Hiroto Ota, Naoya Matsumura, Masahiro Okada, Tetsuya Sugiyama, Hiroshi Saga, Akira Imagawa
Author Information
  1. Yuzo Iwaki: Medicinal Chemistry Research Laboratories,Chemical Process Research Laboratories,Exploratory Research Laboratories,Pharmaceutical Technology Laboratories, and Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
  2. Akira Ohhata: Medicinal Chemistry Research Laboratories,Chemical Process Research Laboratories,Exploratory Research Laboratories,Pharmaceutical Technology Laboratories, and Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
  3. Shingo Nakatani: Medicinal Chemistry Research Laboratories,Chemical Process Research Laboratories,Exploratory Research Laboratories,Pharmaceutical Technology Laboratories, and Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
  4. Katsuya Hisaichi: Medicinal Chemistry Research Laboratories,Chemical Process Research Laboratories,Exploratory Research Laboratories,Pharmaceutical Technology Laboratories, and Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
  5. Yasuyuki Okabe: Medicinal Chemistry Research Laboratories,Chemical Process Research Laboratories,Exploratory Research Laboratories,Pharmaceutical Technology Laboratories, and Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
  6. Atsushi Hiramatsu: Medicinal Chemistry Research Laboratories,Chemical Process Research Laboratories,Exploratory Research Laboratories,Pharmaceutical Technology Laboratories, and Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
  7. Toshihide Watanabe: Medicinal Chemistry Research Laboratories,Chemical Process Research Laboratories,Exploratory Research Laboratories,Pharmaceutical Technology Laboratories, and Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
  8. Shingo Yamamoto: Medicinal Chemistry Research Laboratories,Chemical Process Research Laboratories,Exploratory Research Laboratories,Pharmaceutical Technology Laboratories, and Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
  9. Taihei Nishiyama: Medicinal Chemistry Research Laboratories,Chemical Process Research Laboratories,Exploratory Research Laboratories,Pharmaceutical Technology Laboratories, and Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
  10. Juta Kobayashi: Medicinal Chemistry Research Laboratories,Chemical Process Research Laboratories,Exploratory Research Laboratories,Pharmaceutical Technology Laboratories, and Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
  11. Yasuo Hirooka: Medicinal Chemistry Research Laboratories,Chemical Process Research Laboratories,Exploratory Research Laboratories,Pharmaceutical Technology Laboratories, and Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
  12. Hideki Moriguchi: Medicinal Chemistry Research Laboratories,Chemical Process Research Laboratories,Exploratory Research Laboratories,Pharmaceutical Technology Laboratories, and Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
  13. Tatsuo Maeda: Medicinal Chemistry Research Laboratories,Chemical Process Research Laboratories,Exploratory Research Laboratories,Pharmaceutical Technology Laboratories, and Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
  14. Makoto Katoh: Medicinal Chemistry Research Laboratories,Chemical Process Research Laboratories,Exploratory Research Laboratories,Pharmaceutical Technology Laboratories, and Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
  15. Yuka Komichi: Medicinal Chemistry Research Laboratories,Chemical Process Research Laboratories,Exploratory Research Laboratories,Pharmaceutical Technology Laboratories, and Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
  16. Hiroto Ota: Medicinal Chemistry Research Laboratories,Chemical Process Research Laboratories,Exploratory Research Laboratories,Pharmaceutical Technology Laboratories, and Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
  17. Naoya Matsumura: Medicinal Chemistry Research Laboratories,Chemical Process Research Laboratories,Exploratory Research Laboratories,Pharmaceutical Technology Laboratories, and Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
  18. Masahiro Okada: Medicinal Chemistry Research Laboratories,Chemical Process Research Laboratories,Exploratory Research Laboratories,Pharmaceutical Technology Laboratories, and Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
  19. Tetsuya Sugiyama: Medicinal Chemistry Research Laboratories,Chemical Process Research Laboratories,Exploratory Research Laboratories,Pharmaceutical Technology Laboratories, and Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
  20. Hiroshi Saga: Medicinal Chemistry Research Laboratories,Chemical Process Research Laboratories,Exploratory Research Laboratories,Pharmaceutical Technology Laboratories, and Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
  21. Akira Imagawa: Medicinal Chemistry Research Laboratories,Chemical Process Research Laboratories,Exploratory Research Laboratories,Pharmaceutical Technology Laboratories, and Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
PMID: 32551021 DOI: 10.1021/acsmedchemlett.0c00200

Abstract

Lysophosphatidic acid (LPA) is a bioactive lipid mediator that elicits a number of biological functions, including smooth muscle contraction, cell motility, proliferation, and morphological change. LPA is endogenously produced by Autotaxin (ATX) from extracellular lysophosphatidylcholine (LPC) in plasma. Herein, we report our medicinal chemistry effort to identify a novel and highly potent ATX inhibitor, ONO-8430506 (), with good oral availability. To enhance the enzymatic ATX inhibitory activity, we designed several compounds by structurally comparing our hit compound with the endogenous ligand LPC. Further optimization to improve the pharmacokinetic profile and enhance the ATX inhibitory activity in human plasma resulted in the identification of ONO-8430506 (), which enhanced the antitumor effect of paclitaxel in a breast cancer model.

References

  1. J Med Chem. 2004 Apr 8;47(8):2157-65 [PMID: 15056011]
  2. FASEB J. 2015 Mar;29(3):772-85 [PMID: 25398768]
  3. J Biol Chem. 2002 Oct 18;277(42):39436-42 [PMID: 12176993]
  4. J Biol Chem. 1992 Feb 5;267(4):2524-9 [PMID: 1733949]
  5. PLoS One. 2014 Apr 18;9(4):e93230 [PMID: 24747415]
  6. Bioorg Med Chem Lett. 2017 Oct 15;27(20):4770-4776 [PMID: 28943042]
  7. J Biol Chem. 2006 Sep 1;281(35):25822-30 [PMID: 16829511]
  8. J Biol Chem. 1994 Dec 2;269(48):30479-84 [PMID: 7982964]
  9. Expert Opin Ther Pat. 2017 Jul;27(7):815-829 [PMID: 28447479]
  10. Mol Pain. 2010 Nov 09;6:78 [PMID: 21062487]
  11. Expert Opin Ther Pat. 2013 Sep;23(9):1123-32 [PMID: 23641951]
  12. Future Med Chem. 2014 May;6(8):885-901 [PMID: 24962281]
  13. Bioorg Med Chem Lett. 2010 Apr 1;20(7):2311-5 [PMID: 20207138]
  14. ACS Med Chem Lett. 2017 Dec 20;9(2):89-93 [PMID: 29456793]
  15. Oncogene. 2009 Feb 19;28(7):1028-39 [PMID: 19079345]
  16. ACS Med Chem Lett. 2014 Sep 08;5(10):1082-7 [PMID: 25349648]
  17. Biochim Biophys Acta. 2013 Jan;1831(1):74-85 [PMID: 22954454]
  18. J Exp Med. 2012 May 7;209(5):925-33 [PMID: 22493518]
  19. Nat Struct Mol Biol. 2011 Feb;18(2):205-12 [PMID: 21240269]
  20. J Cell Biol. 2002 Jul 22;158(2):227-33 [PMID: 12119361]
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Word Cloud

Created with Highcharts 10.0.0ATXLPALPCplasmaONO-8430506enhanceinhibitoryactivityLysophosphatidicacidbioactivelipidmediatorelicitsnumberbiologicalfunctionsincludingsmoothmusclecontractioncellmotilityproliferationmorphologicalchangeendogenouslyproducedautotaxinextracellularlysophosphatidylcholineHereinreportmedicinalchemistryeffortidentifynovelhighlypotentinhibitorgoodoralavailabilityenzymaticdesignedseveralcompoundsstructurallycomparinghitcompoundendogenousligandoptimizationimprovepharmacokineticprofilehumanresultedidentificationenhancedantitumoreffectpaclitaxelbreastcancermodelONO-8430506:NovelAutotaxinInhibitorEnhancesAntitumorEffectPaclitaxelBreastCancerModel

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