title: 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.
abstract: 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.
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Menichincheri
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Ardini
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Magnaghi
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Nilla
authors.initials: N
authors.lastname: Avanzi
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Banfi
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bossi
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Buffa
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Canevari
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Ceriani
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Maristella
authors.initials: M
authors.lastname: Colombo
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Corti
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Donati
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Fasolini
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Eduard
authors.initials: E
authors.lastname: Felder
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Fiorelli
authors.affiliation: Accelera Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Fiorentini
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Arturo
authors.initials: A
authors.lastname: Galvani
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Isacchi
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Andrea Lombardi
authors.initials: AL
authors.lastname: Borgia
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Marchionni
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Nesi
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Christian
authors.initials: C
authors.lastname: Orrenius
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Achille
authors.initials: A
authors.lastname: Panzeri
authors.affiliation: Accelera Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Pesenti
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Rusconi
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Maria Beatrice
authors.initials: MB
authors.lastname: Saccardo
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Ermes
authors.initials: E
authors.lastname: Vanotti
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Perrone
authors.affiliation: Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Orsini
mesh_terms: D000284:Administration, Oral; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects; D015153:Blotting, Western; D002463:Cell Membrane Permeability / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003460:Crystallization; D018360:Crystallography, X-Ray; D004285:Dogs; D055808:Drug Discovery; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D008862:Microsomes, Liver / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D020917:Receptor, trkA / Q000037:antagonists & inhibitors; D020813:Receptor, trkB / Q000037:antagonists & inhibitors; D020812:Receptor, trkC / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C000626173:ALK protein, human; C000626174:Alk protein, mouse; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D020813:Receptor, trkB; D020812:Receptor, trkC; C000607349:entrectinib