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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• 作者：Maria Menichincheri ; Elena Ardini ; Paola Magnaghi ; Nilla Avanzi ; Patrizia Banfi ; Roberto Bossi ; Laura Buffa ; Giulia Canevari ; Lucio Ceriani ; Maristella Colombo ; Luca Corti ; Daniele Donati ; Marina Fasolini ; Eduard Felder ; Claudio Fiorelli ; Francesco Fiorentini ; Arturo Galvani ; Antonella Isacchi ; Andrea Lombardi Borgia ; Chiara Marchionni ; Marcella Nesi ; Christian Orrenius ; Achille Panzeri ; Enrico Pesenti ; Luisa Rusconi ; Maria Beatrice Saccardo ; Ermes Vanotti ; Ettore Perrone ; Paolo Orsini
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：April 14, 2016
• 年：2016
• 卷：59
• 期：7
• 页码：3392-3408
• 全文大小：749K
• 年卷期：0
• ISSN：1520-4804

文摘

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.