ONO-8430506: A Novel Autotaxin Inhibitor That Enhances the Antitumor Effect of Paclitaxel in a Breast Cancer Model
| Autor: | Atsushi Hiramatsu, Hiroto Ota, Makoto Katoh, Shingo Nakatani, Taihei Nishiyama, Masahiro Okada, Hiroshi Saga, Juta Kobayashi, Toshihide Watanabe, Tatsuo Maeda, Naoya Matsumura, Shingo Yamamoto, Akira Imagawa, Katsuya Hisaichi, Hideki Moriguchi, Yuka Komichi, Yuzo Iwaki, Tetsuya Sugiyama, Hirooka Yasuo, Yasuyuki Okabe, Akira Ohhata |
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| Rok vydání: | 2020 |
| Předmět: |
010405 organic chemistry
Organic Chemistry Motility Smooth muscle contraction Breast Cancer Model 01 natural sciences Biochemistry Bioactive lipid 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry.chemical_compound Mediator chemistry Paclitaxel Drug Discovery Lysophosphatidic acid Cancer research lipids (amino acids peptides and proteins) sense organs Autotaxin |
| Zdroj: | ACS Med Chem Lett |
| ISSN: | 1948-5875 |
| Popis: | [Image: see text] 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. |
| Databáze: | OpenAIRE |
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