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

Article abstract of DOI:10.1021/acsmedchemlett.0c00200

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.

Full text of DOI:10.1021/acsmedchemlett.0c00200

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Letter
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, and Akira Imagawa
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.0c00200 • Publication Date (Web): 14 May 2020
Downloaded from pubs.acs.org on May 14, 2020
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ACS Medicinal Chemistry Letters
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ACS Medicinal Chemistry Letters
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