Discovery of (10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase (ALK) and c-ros Oncogene 1 (ROS1) with Preclinical Brain Exposure and Broad-Spectrum Potency against ALK-Resistant Mutations
Discovery of (10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase (ALK) and c-ros Oncogene 1 (ROS1) with Preclinical Brain Exposure and Broad-Spectrum Potency against ALK-Resistant Mutations
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DOI：
10.1021/jm500261q
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发表时间：
2014-06-12
影响因子：
7.3
通讯作者：
Edwards, Martin P.
中科院分区：
文献类型：
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作者：
Johnson, Ted W.;Richardson, Paul F.;Edwards, Martin P.
尽管Crizotinib在间变性淋巴瘤激酶(ALK)阳性的非小细胞肺癌患者中显示出强大的疗效，但在治疗过程中最终会出现进展。耐药患者样本显示了ALK激活域的各种点突变，包括L1196M关守突变。此外，一些患者的病情进展是由于脑内的癌症转移。通过基于结构的药物设计、亲脂效率和基于物理性质的优化，制备了高效的大环ALK抑制剂，具有良好的吸收、分布、代谢和排泄(ADME)，较低的P-糖蛋白1介导的外排倾向和良好的被动通透性。这些结构上不寻常的大环类抑制剂对野生型ALK和临床报道的ALK激活域突变具有很强的抑制作用。克服了重大的合成挑战，利用新的转化使这些大环能够在药物发现范例中使用。这项工作导致了8K(PF-06463922)的发现，它结合了广谱活性、中枢神经系统ADME和高度的激酶选择性。
Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocydic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocydic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.