Discovery of Entrectinib: A New 3-Aminoindazole As a Potent Anaplastic Lymphoma Kinase (ALK), c-ros Oncogene 1 Kinase (ROS1), and Pan-Tropomyosin Receptor Kinases (Pan-TRKs) inhibitor
Discovery of Entrectinib: A New 3-Aminoindazole As a Potent Anaplastic Lymphoma Kinase (ALK), c-ros Oncogene 1 Kinase (ROS1), and Pan-Tropomyosin Receptor Kinases (Pan-TRKs) inhibitor
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DOI：
10.1021/acs.jmedchem.6b00064
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发表时间：
2016-04-14
影响因子：
7.3
通讯作者：
Orsini, Paolo
中科院分区：
文献类型：
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作者：
Menichincheri, Maria;Ardini, Elena;Orsini, Paolo
间变性淋巴瘤激酶（ALK）是一种受体酪氨酸激酶，负责不同类型肿瘤的发展。尽管2011年批准的第一种ALK抑制剂克唑替尼（Xalkori）具有显著的临床活性，但耐药突变和脑转移的出现经常导致患者复发。在我们的ALK药物发现计划中，我们鉴定了化合物1，一种在生化和细胞测定中对ALK具有活性的新型3-氨基吲唑。其优化导致化合物2（恩曲替尼），一种对ALK依赖性细胞系具有活性的有效口服ALK抑制剂，在不同动物物种中有效渗透血脑屏障（BBB），并且在体内异种移植模型中高度有效。此外，恩曲替尼对最近发现在几种肿瘤类型中组成性激活的密切相关的酪氨酸激酶ROS 1和TRKs具有严格的效力。Entrectinib目前正在进行I/II期临床试验，用于治疗受ALK，ROS 1和TRK阳性肿瘤影响的患者。
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for the development of different tumor types. Despite the remarkable clinical activity of crizotinib (Xalkori), the first ALK inhibitor approved in 2011, the emergence of resistance mutations and of brain metastases frequently causes relapse in patients. Within our ALK drug discovery program, we identified compound 1, a novel 3-aminoindazole active on ALK in biochemical and in cellular assays. Its optimization led to compound 2 (entrectinib), a potent orally available ALK inhibitor active on ALK-dependent cell lines, efficiently penetrant the blood-brain barrier (BBB) in different animal species and highly efficacious in in vivo xenograft models. Moreover, entrectinib resulted to be strictly potent on the closely related tyrosine kinases ROS1 and TRKs recently found constitutively activated in several tumor types. Entrectinib is currently undergoing phase I/II clinical trial for the treatment of patients affected by ALK-, ROS1-, and TRK-positive tumors.