Discovery of AZD8931, an Equipotent, Reversible Inhibitor of Signaling by EGFR, HER2, and HER3 Receptors
Discovery of AZD8931, an Equipotent, Reversible Inhibitor of Signaling by EGFR, HER2, and HER3 Receptors
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DOI：
10.1021/ml400146c
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发表时间：
2013-08-01
影响因子：
4.2
通讯作者：
Ogilvie, Donald
中科院分区：
文献类型：
--
作者：
Barlaam, Bernard;Anderton, Judith;Ogilvie, Donald
HER家族信号的失调促进了肿瘤细胞的增殖和存活，并在许多人类癌症中得到了描述。同时，EGFR-、HER2-和her3介导的信号的等效抑制可能在选择性EGFR或HER2治疗药物无效或仅适度有效的癌症环境中具有临床应用价值。我们描述了AZD8931(2)的发现，AZD8931是EGFR-， HER2-和her3介导的信号传导的等效，可逆抑制剂，以及该系列中的结构-活性关系。基于HER2激酶结构域模型的对接研究有助于解释AZD8931中甲基乙酰胺侧链中HER2活性增加的原因。AZD8931在临床前物种中表现出良好的药代动力学，与剂量类似物相比，在LoVo肿瘤生长功效模型中表现出更高的活性。AZD8931目前正在进行癌症治疗的人体临床试验评估。
Deregulation of HER family signaling promotes proliferation and tumor cell survival and has been described in many human cancers. Simultaneous, equipotent inhibition of EGFR-, HER2-, and HER3-mediated signaling may be of clinical utility in cancer settings where the selective EGFR or HER2 therapeutic agents are ineffective or only modestly active. We describe the discovery of AZD8931 (2), an equipotent, reversible inhibitor of EGFR-, HER2-, and HER3-mediated signaling and the structure-activity relationships within this series. Docking studies based on a model of the HER2 kinase domain helped rationalize the increased HER2 activity seen with the methyl acetamide side chain present in AZD8931. AZD8931 exhibited good pharmacokinetics in preclinical species and showed superior activity in the LoVo tumor growth efficacy model compared to dose analogues. AZD8931 is currently being evaluated in human clinical trials for the treatment of cancer.