Pharmacodynamics of 2-{4-[(1E)-1-(Hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-3-(pyridine-4-yl)-1H-pyrazol-1-yl}ethan-1-ol (GDC-0879), a Potent and Selective B-Raf Kinase Inhibitor: Understanding Relationships between Systemic Concentrations, Phosphorylated Mitogen-Activated Protein Kinase Kinase 1 Inh
Pharmacodynamics of 2-{4-[(1E)-1-(Hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-3-(pyridine-4-yl)-1H-pyrazol-1-yl}ethan-1-ol (GDC-0879), a Potent and Selective B-Raf Kinase Inhibitor: Understanding Relationships between Systemic Concentrations, Phosphorylated Mitogen-Activated Protein Kinase Kinase 1 Inh
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2-{4-[(1E)-1-(羟基亚氨基)-2,3-二氢-1H-茚-5-基]-3-(吡啶-4-基)-1H-吡唑-1-基的药效学
DOI：
10.1124/jpet.108.148189
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发表时间：
2009
影响因子：
3.5
通讯作者：
E. Choo
中科院分区：
文献类型：
--
作者：
H. Wong;M. Belvin;S. Herter;K. Hoeflich;Lesley J. Murray;L. Wong;E. Choo
Raf/丝裂原活化蛋白激酶激酶（MEK）/细胞外信号调节激酶信号传导途径参与与肿瘤发生相关的细胞应答，包括细胞增殖、侵袭、存活和血管生成。2-{4-[（1 E）-1-（羟基亚氨基）-2，3-二氢-1H-茚-5-基]-3-（吡啶-4-基）-1H-吡唑-1-基}乙-1-醇（GDC-0879）是一种新型的、有效的、选择性的B-Raf抑制剂。本研究的目的是表征GDC-0879血浆浓度与A375黑色素瘤和Colo 205结肠癌异种移植物中肿瘤生长抑制之间的关系，并了解与A375异种移植物中肿瘤生长抑制相关的药效学（PD）标志物反应要求[磷酸化（p）MEK 1抑制]。通过将肿瘤数据拟合至间接应答模型获得的肿瘤停滞所需的GDC-0879血浆浓度估计值相当，A375和Colo 205异种移植物分别为4.48和3.27 μM。这与GDC-0879在两种细胞系中的相当体外效力一致。经口给予35、50和100 mg/kg后，在A375异种移植物中表征了肿瘤中GDC-0879血浆浓度与pMEK 1抑制之间的关系。将pMEK 1抑制作用拟合至间接响应模型，得出IC 50估计值为3.06 μM。使用综合药代动力学-PD模型，将pMEK 1抑制进一步与来自9种不同GDC-0879给药方案的A375肿瘤体积数据相关联。使用从该模型估计的药效学参数生成的K（描述肿瘤生长抑制的速率常数）与pMEK 1抑制的模拟PD标志物响应曲线图显示，pMEK 1抑制-响应曲线陡峭，与估计的Hill系数10.8一致。在用GDC-0879处理的A375异种移植物中，肿瘤生长抑制需要>40% pMEKl抑制的阈值，并且停滞需要最少约60% pMEKl抑制。
The Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase signaling pathway is involved in cellular responses relevant to tumorigenesis, including cell proliferation, invasion, survival, and angiogenesis. 2-{4-[(1E)-1-(Hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-3-(pyridine-4-yl)-1H-pyrazol-1-yl}ethan-1-ol (GDC-0879) is a novel, potent, and selective B-Raf inhibitor. The objective of this study was to characterize the relationship between GDC-0879 plasma concentrations and tumor growth inhibition in A375 melanoma and Colo205 colon cancer xenografts and to understand the pharmacodynamic (PD) marker response requirements [phosphorylated (p)MEK1 inhibition] associated with tumor growth inhibition in A375 xenografts. Estimates of GDC-0879 plasma concentrations required for tumor stasis obtained from fitting tumor data to indirect response models were comparable, at 4.48 and 3.27 μM for A375 and Colo205 xenografts, respectively. This was consistent with comparable in vitro potency of GDC-0879 in both cell lines. The relationship between GDC-0879 plasma concentrations and pMEK1 inhibition in the tumor was characterized in A375 xenografts after oral doses of 35, 50, and 100 mg/kg. Fitting pMEK1 inhibition to an indirect response model provided an IC50 estimate of 3.06 μM. pMEK1 inhibition was further linked to A375 tumor volume data from nine different GDC-0879 dosing regimens using an integrated pharmacokinetic-PD model. A simulated PD marker response curve plot of K (rate constant describing tumor growth inhibition) versus pMEK1 inhibition generated using pharmacodynamic parameters estimated from this model, showed a steep pMEK1 inhibition-response curve consistent with an estimated Hill coefficient of ≅8. A threshold of >40% pMEK1 inhibition is required for tumor growth inhibition, and a minimum of ∼60% pMEK1 inhibition is required for stasis in A375 xenografts treated with GDC-0879.
DOI：
10.1073/pnas.93.19.10078
发表时间：
1996-09-17
影响因子：
11.1
作者：
Huang, CYF;Ferrell, JE
通讯作者：
Ferrell, JE