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

Menichincheri, Maria; Ardini, Elena; Magnaghi, Paola; Avanzi, Nilla; Banfi, Patrizia; Bossi, R.; Buffa, Laura; Canevari, Giulia; Ceriani, Lucio; Colombo, Maristella; Corti, Luca; Donati, Daniele; Fasolini, Marina; Felder, E.; Fiorelli, Claudio; Fiorentini, Francesco; Galvani, Arturo; Isacchi, Antonella; Borgia, Andrea; Marchionni, Chiara; Nesi, Marcella; Orrenius, Christian; Panzeri, A.; Pesenti, Enrico; Rusconi, Luisa; Saccardo, Maria Beatrice; Vanotti, Ermes; Perrone, Ettore; Orsini, Paolo

doi:10.1021/acs.jmedchem.6b00064

Cited by 223 publications

(159 citation statements)

References 46 publications

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“…Using the Entrectinib:ALK structure (5FTO) as a model of active site inhibitors, we can also predict other residues that, when mutated, could affect our compounds within the new binding site (33). We predict four residues-Phe-589, Gly-667, Asp-668, and Phe-669-by identifying residues within 5 Å of both Entrectinib and compound 1 in TrkA.…”

Section: Discussionmentioning

confidence: 99%

Structural characterization of nonactive site, TrkA-selective kinase inhibitors

Su¹,

Rickert

Burlein

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Current therapies for chronic pain can have insufficient efficacy and lead to side effects, necessitating research of novel targets against pain. Although originally identified as an oncogene, Tropomyosinrelated kinase A (TrkA) is linked to pain and elevated levels of NGF (the ligand for TrkA) are associated with chronic pain. Antibodies that block TrkA interaction with its ligand, NGF, are in clinical trials for pain relief. Here, we describe the identification of TrkA-specific inhibitors and the structural basis for their selectivity over other Trk family kinases. The X-ray structures reveal a binding site outside the kinase active site that uses residues from the kinase domain and the juxtamembrane region. Three modes of binding with the juxtamembrane region are characterized through a series of ligand-bound complexes. The structures indicate a critical pharmacophore on the compounds that leads to the distinct binding modes. The mode of interaction can allow TrkA selectivity over TrkB and TrkC or promiscuous, pan-Trk inhibition. This finding highlights the difficulty in characterizing the structure-activity relationship of a chemical series in the absence of structural information because of substantial differences in the interacting residues. These structures illustrate the flexibility of binding to sequences outside of-but adjacent to-the kinase domain of TrkA. This knowledge allows development of compounds with specificity for TrkA or the family of Trk proteins.TrkA | kinase | pain | inhibition | selectivity

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Section: Discussionmentioning

confidence: 99%

Structural characterization of nonactive site, TrkA-selective kinase inhibitors

Su¹,

Rickert

Burlein

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Entrectinib inhibits TRK in addition to ROS1 and ALK (132, 133). Updated results from a phase I study of entrectinib showed significant responses in TKI-naïve patients with NTRK -, ROS1 -, and ALK1 -rearranged solid tumors (confirmed ORR of 100%, 86%, and 57%, respectively) (134).…”

Section: Developing Strategies To Overcome Resistancementioning

confidence: 99%

Targeting ALK: Precision Medicine Takes on Drug Resistance

2017

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Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK-rearranged malignancies, including non-small-cell lung cancer (NSCLC). However, the clinical benefit of targeting ALK using tyrosine kinase inhibitors (TKIs) is almost universally limited by the emergence of drug resistance. Diverse mechanisms of resistance to ALK TKIs have now been discovered, and these basic mechanisms are informing the development of novel therapeutic strategies to overcome resistance in the clinic. In this Review, we summarize the current successes and challenges of targeting ALK.

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“…Entrectinib is an oral inhibitor with low nanomolar potency against ALK, ROS1, and TRK kinases in enzymatic assays (85), and is able to effectively penetrate the blood-brain barrier (86). Its cellular IC 50 against ROS1 in Ba/F3 models is ~5 nM (86).…”

Section: Ros1-targeted Therapies In Lung Cancermentioning

confidence: 99%

Recent Advances in Targeting ROS1 in Lung Cancer

Lin

Shaw

2017

Journal of Thoracic Oncology

199

201

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ROS1 is a validated therapeutic target in non-small cell lung cancer (NSCLC). In a phase I study, the multi-targeted MET/ALK/ROS1 inhibitor crizotinib demonstrated remarkable efficacy in ROS1-rearranged NSCLCs, and consequently gained approval by the United States Food and Drug Administration as well as the European Medicines Agency in 2016. However, similar to other oncogene-driven lung cancers, ROS1-rearranged lung cancers treated with crizotinib eventually acquire resistance, leading to disease relapse. Novel ROS1 inhibitors and therapeutic strategies are therefore needed. Insights into the mechanisms of resistance to ROS1-directed tyrosine kinase inhibitors (TKIs) are now beginning to emerge and are helping to guide the development of new ROS1 inhibitors. This review discusses the biology and diagnosis of ROS1-rearranged NSCLC, and current and emerging treatment options for this disease. Future challenges in the field are highlighted.

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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

Cited by 223 publications

References 46 publications

Structural characterization of nonactive site, TrkA-selective kinase inhibitors

Structural characterization of nonactive site, TrkA-selective kinase inhibitors

Targeting ALK: Precision Medicine Takes on Drug Resistance

Recent Advances in Targeting ROS1 in Lung Cancer

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