ONO-8430506

ONO-8430506 is an orally bioavailable and potent autotaxin (ATX)/ENPP2 inhibitor with the IC 90 of 100 nM for ATX activity in mouse plasma . In Vitro Autotaxin, also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), is a secreted enzyme that has lysophospholipase D activity. The IC 50 s of ONO-8430506 for the lysophospholipase D (LysoPLD) activity of recombinant human ATX/ENPP2 are 5.1 nM in an assay using synthetic fluorescent substrate (FS-3) and 4.5 nM in an assay using a natural substrate (16:0-LPC). ONO-8430506 shows efficient inhibition of lysophosphatidic acid (LPA) formation, with IC 50 s of approximately 10 nM with both recombinant and plasma derived ATX/ENPP2 from various animal species. MCE has not independently confirmed the accuracy of these methods. They are for reference only. In Vivo ONO-8430506 (10 mg/kg/day; gavage; for 21 days) slows initial tumor growth and limits lung metastasis . ONO-8430506 decreases the initial phase of breast tumor growth and subsequent lung metastases by ~60% in a syngeneic orthotopic mouse model . ONO-8430506 (oral; 30 mg/kg) demonstrates good pharmacokinetics and persistently inhibits plasma lysophosphatidic acid formation in rats. ONO-8430506 (30 or 100 mg/kg) enhances the antitumor effect of Paclitaxel in a breast cancer model. ONO-8430506 exhibits moderate oral bioavailability (rat 51.6%, dog 71.1%, and monkey 30.8%) and C max (rat 261, dog 1670, and monkey 63 ng/mL) following oral administration (rat 1, dog 1, and monkey 1 mg/kg). ONO-8430506 exhibits terminal elimination half-lives (rat 3.4, dog 8.9, and monkey 7.9 h) due to low plasma clearance (8.2, 4.7, and 5.8 mL/min/kg respectively) combined with large volumes of distribution (1474, 1863, and 2275 mL/kg respectively) following intravenous administration (rat 0.3, dog 0.3, and monkey 0.3 mg/kg). MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: Female BALB/c mice, 8-10 wk old (BALB/cAnNCrl) Dosage: 10 mg/kg Administration: Gavaged daily for 21 days; 10 μL/g Result: Tumor growth in ONO-8430506-treated mice caught up to the vehicle group by day 13; thereafter, primary tumor size was not significantly different from the vehicle-treated mice. However, treatment with ONO-8430506 decreased the numbers of metastatic nodules in the lungs at day 21 by ~60%. Form:Solid

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