AZD8186

型号：

产品价格：电议采购度：1619 原产地：美洲

发布时间：2021/6/22 9:07:16 所属地区：国外国外

简要描述：

AZD8186 是一种 PI3K 抑制剂，抑制 PI3Kβ (IC5050=4 nM)，PI3Kδ (IC5050=12 nM)，PI3Kα (IC50=35 nM) 和 PI3Kγ (IC50=675 nM)。

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AZD8186

CAS No. : 1627494-13-6

MCE 站：AZD8186

产品活性：AZD8186 是一种 PI3K 抑制剂，抑制 PI3Kβ (IC50₅₀=4 nM)，PI3Kδ (IC50₅₀=12 nM)，PI3Kα (IC₅₀=35 nM) 和 PI3Kγ (IC₅₀=675 nM)。

研究领域：PI3K/Akt/mTOR

作用靶点：PI3K

In Vitro: AZD8186 is a potent inhibitor of PI3Kβ with additional activity versus the PI3Kδ isoform. Tight-binding kinetics of AZD8186 means biochemical assays underestimate the absolute selectivity profile for PI3Ks. In a broad panel of protein ａnd lipid kinase assays selectivity for PI3Kβ ａnd δ is >100-fold versus 74 protein ａnd lipid kinases. At 10 μM, AZD8186 had no significant binding to 442 other kinases in a KinomeScan screen. AZD8186 shows selectivity for PI3K family kinases, no other off-target activity is detected. In the PTEN-null line, MDA-MB-468 AZD8186 inhibits PI3Kβ-dependent activation of pAKT (Ser473) with an IC₅₀ value of 3 nM. Potency in the PIK3CA-mutant line BT474c is 752 nM demonstrating selectivity for PI3Kβ over PI3Kα. IgM mediated stimulation of B cells results in phosphorylation of AKT through activation of PI3Kδ. AZD8186 inhibits IgM-stimulated phosphorylation of pAKT (Ser473) activation in JEKO cells with an IC₅₀ value of 17 nM. In cell proliferation assays, AZD8186 inhibits proliferation of MDA-MB-468 cells with a GI₅₀ value of 65 nM, IgM stimulated JEKO cell growth with an IC₅₀ value of 228 nM. It only inhibited BT474c cell growth with an IC₅₀ value of 1.981 μM consistent with its selectivity for PI3Kβ over PI3Kα.

In Vivo: To assess single-agent efficacy of AZD8186 in vivo, antitumor activity is assessed in the PTEN-null TNBC models HCC70 ａnd MDA-MB-468, ａnd the prostate models PC3 ａnd HID28. At 50 ａnd 25 mg/kg twice a day, AZD8186 inhibits the growth of all four models. At 25 ａnd 50 mg/kg, HCC70 is inhibited at 62% (P<0.001) ａnd 85% (P<0.001), respectively, MDA-MB-468 is inhibited at 47% (P<0.001) ａnd 76% (P<0.001), respectively, at end at of study, with regression early in the study. Efficacy in the PTEN-null prostate model, PC3 is less pronounced with 25 ａnd 50 mg/kg giving maximal growth inhibition of 59% (P<0.001) ａnd 64% (P<0.001), respectively. In contrast, AZD8186 gives 79% (P<0.001) growth inhibition in the PTEN-null prostate explant model HID28. In mouse, AZD8186 has a short half-life delivering a PK profile that results in intermittent cover over a 24 hours dosing interval. To increase the time of exposure, animals bearing PC3 tumors are co-dosed with AZD8186 in the presence of the Cyt P450 inhibitor ABT, which results in significantly increased exposure. This also increased the efficacy in the PC3 model with 86% (P<0.005) reduction in tumor growth achieved with 30 mg/kg AZD8186+ABT.

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更新时间：2024/1/2 10:12:11

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