Preclinical study demonstrates that novel autotaxin inhibitor ONO-8430506 augments paclitaxel efficacy in breast cancer models, suggesting therapeutic promise for combination treatment.
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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Iwaki et al. (2020) studied this question.
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