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.
Subject(s)
Antineoplastic Agents/pharmacology , Benzamides/pharmacology , Drug Discovery , Indazoles/pharmacology , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Administration, Oral , Anaplastic Lymphoma Kinase , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Benzamides/administration & dosage , Benzamides/chemistry , Blood-Brain Barrier/drug effects , Blotting, Western , Cell Membrane Permeability/drug effects , Cell Proliferation/drug effects , Crystallization , Crystallography, X-Ray , Dogs , Humans , Indazoles/administration & dosage , Indazoles/chemistry , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice , Mice, Nude , Mice, SCID , Microsomes, Liver/drug effects , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins/antagonists & inhibitors , Rats , Rats, Wistar , Receptor, trkA/antagonists & inhibitors , Receptor, trkB/antagonists & inhibitors , Receptor, trkC/antagonists & inhibitors , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
We have recently reported a new class of CDK2/cyclin A inhibitors based on a bicyclic tetrahydropyrrolo[3,4-c]pyrazole scaffold. The introduction of small alkyl or cycloalkyl groups in position 6 of this scaffold allowed variation at the other two diversity points. Conventional and polymer-assisted solution phase chemistry provided a way of generating compounds with improved biochemical and cellular activity. Optimization of the physical properties and pharmacokinetic profile led to a compound which exhibited good efficacy in vivo on A2780 human ovarian carcinoma.
