Open AccessONO-8430506: A Novel Autotaxin Inhibitor That Enhances the Antitumor Effect of Paclitaxel in a Breast Cancer Model
Author(s) -
Yuzo Iwaki,
Akira Ohhata,
Shingo Nakatani,
Katsuya Hisaichi,
Yasuyuki Okabe,
Atsushi Hiramatsu,
Toshihide Watanabe,
Shingo Yamamoto,
Taihei Nishiyama,
Juta Kobayashi,
Yasuo Hirooka,
Hideki Moriguchi,
Takeyasu Maeda,
Makoto Katoh,
Yuka Komichi,
Hiroto Ota,
Naoya Matsumura,
Masahiro Okada,
Tetsuya Sugiyama,
Hiroshi Saga,
Akira Imagawa
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00200
Subject(s) - autotaxin , lysophosphatidic acid , lysophosphatidylcholine , paclitaxel , chemistry , motility , pharmacology , extracellular , cancer cell , breast cancer , cancer research , biochemistry , receptor , cancer , microbiology and biotechnology , biology , phospholipid , medicine , membrane , phosphatidylcholine
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.