Synthesis, Structure–Activity Relationships, and in Vivo Efficacy of the Novel Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor 5-Chloro-<i>N</i>2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-<i>N</i>4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) Currently in Phase 1 and Phase 2 Clinical Trials

Marsilje, Thomas H.; Pei, Wei; Chen, Bei; Lu, Wei; Uno, Tetsuo; Jin, Yunho; Jiang, Tao; Kim, Sung-Joon; Li, Nanxin; Warmuth, Markus; Sarkisova, Yelena; Sun, Frank F.; Steffy, Auzon; Pferdekamper, AnneMarie Culazzo; Li, Allen G.; Joseph, Sean B.; Kim, Young; Liu, Bo; Tuntland, Tove; Cui, Xiaoming; Gray, Nathanael S.; Steensma, Ruo W.; Wan, Yufeng; Jiang, Jiaoyang; Chopiuk, Greg; Li, Jie; Gordon, W. Perry; Richmond, Wendy; Johnson, Kevin C.; Chang, Jonathan; Groessl, Todd; He, You-Qun; Phimister, Andrew; Aycinena, J. Alex; Lee, Christian C.; Bursulaya, Badry; Karanewsky, Donald S.; Seidel, H. Martin; Harris, Jennifer L.; Michellys, Pierre‐Yves

doi:10.1021/jm400402q

Cited by 366 publications

(307 citation statements)

References 44 publications

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“…In addition, in treatment-na€ ve H228 xenograft models, ceritinib demonstrated more durable antitumor activity than crizotinib (13). The kinase selectivity has been tested in a cellular proliferation assay against 16 different kinases, and aside from ALK, no inhibition below 100 nmol/L was observed (14). Unlike crizotinib, ceritinib does not inhibit the activity of MET, a tyrosine kinase that can be overexpressed, amplified, or mutated in NSCLC, leading to cell progression and survival.…”

Section: Ceritinibmentioning

confidence: 99%

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Ceritinib for the Treatment of Late-Stage (Metastatic) Non–Small Cell Lung Cancer

Massarelli

Papadimitrakopoulou

2015

Clinical Cancer Research

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Over the past decade, the non-small cell lung cancer therapeutics landscape has been dominated by the increasing focus on identification and validation of molecular targets, as well as the identification of the best candidate agents to address these targets. Among the notable successes have been the approval of erlotinib, gefitinib, and afatinib for the EGFR mutation, and more recently crizotinib for anaplastic lymphoma kinase (ALK) gene rearrangement. Despite the excellent efficacy of crizotinib, several mechanisms of resistance, including secondary mutation in the ALK gene, eventually result in disease progression, and several second-generation ALK inhibitors, notably ceritinib, have demonstrated evidence of clinical activity in this setting. This review discusses the data associated with the recent accelerated approval of ceritinib for treatment of patients with ALK-positive, metastatic lung adenocarcinoma with disease progression on or who are intolerant to crizotinib.

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Section: Ceritinibmentioning

confidence: 99%

“…However, second-generation ALKi has selective activity against ALK-TK and does not demonstrate activity against MET-TK. Second-generation ALKi, such as alectinib (25,26) and ceritinib (14), have been shown to be effective not only in crizotinib-na € ve patients, but also in those resistant to crizotinib.…”

Section: Mechanisms Of Resistance To Alk Inhibitorsmentioning

confidence: 99%

Ceritinib for the Treatment of Late-Stage (Metastatic) Non–Small Cell Lung Cancer

Massarelli

Papadimitrakopoulou

2015

Clinical Cancer Research

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“…However, the observation that about one third of ALK-positive NSCLC patients progresses after initial clinical response to the drug due to the acquisition of secondary mutations (21)(22)(23), together with the apparently poor ability of crizotinib to reach effective concentrations beyond the blood-brain barrier (BBB; ref. 24), have prompted the clinical development of several "second-generation" ALK inhibitors, such as ceritinib (25) and alectinib (26).…”

Section: Introductionmentioning

confidence: 99%

Entrectinib, a Pan–TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications

Ardini

Menichincheri

Banfi

et al. 2016

Molecular Cancer Therapeutics

259

191

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Activated ALK and ROS1 tyrosine kinases, resulting from chromosomal rearrangements, occur in a subset of non-small cell lung cancers (NSCLC) as well as other tumor types and their oncogenic relevance as actionable targets has been demonstrated by the efficacy of selective kinase inhibitors such as crizotinib, ceritinib, and alectinib. More recently, low-frequency rearrangements of TRK kinases have been described in NSCLC, colorectal carcinoma, glioblastoma, and Spitzoid melanoma. Entrectinib, whose discovery and preclinical characterization are reported herein, is a novel, potent inhibitor of ALK, ROS1, and, importantly, of TRK family kinases, which shows promise for therapy of tumors bearing oncogenic forms of these proteins. Proliferation profiling against over 200 human tumor cell lines revealed that entrectinib is exquisitely potent in vitro against lines that are dependent on the drug's pharmacologic targets. Oral administration of entrectinib to tumor-bearing mice induced regression in relevant human xenograft tumors, including the TRKA-dependent colorectal carcinoma KM12, ROS1-driven tumors, and several ALK-dependent models of different tissue origins, including a model of brain-localized lung cancer metastasis. Entrectinib is currently showing great promise in phase I/II clinical trials, including the first documented objective responses to a TRK inhibitor in colorectal carcinoma and in NSCLC. The drug is, thus, potentially suited to the therapy of several molecularly defined cancer settings, especially that of TRK-dependent tumors, for which no approved drugs are currently available.

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“…210 Moreover, ceritinib has been shown to be effective in patients with crizotinib-resistant NSCLC. 211 In a phase I trial evaluating ceritinib in patients with advanced or metastatic ALK-altered tumors (ASCEND-1), three patients with relapsed ALK-positive ALCL were enrolled.…”

Section: Alk Inhibitorsmentioning

confidence: 99%