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

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

  • ACS Med Chem Lett. 2020 May 14;11(6):1335-1341. doi: 10.1021/acsmedchemlett.0c00200.
Yuzo Iwaki 1,  Akira Ohhata 1,  Shingo Nakatani 1,  Katsuya Hisaichi 1,  Yasuyuki Okabe 1,  Atsushi Hiramatsu 1,  Toshihide Watanabe 1,  Shingo Yamamoto 1,  Taihei Nishiyama 1,  Juta Kobayashi 1,  Yasuo Hirooka 1,  Hideki Moriguchi 1,  Tatsuo Maeda 1,  Makoto Katoh 1,  Yuka Komichi 1,  Hiroto Ota 1,  Naoya Matsumura 1,  Masahiro Okada 1,  Tetsuya Sugiyama 1,  Hiroshi Saga 1,  Akira Imagawa 1
Affiliations

Affiliation

  • 1 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 (20), 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 (20), which enhanced the antitumor effect of paclitaxel in a breast Cancer model.

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