Design and synthesis of a highly selective, orally active and potent anaplastic lymphoma kinase inhibitor (CH5424802)

Kinoshita, Kazutomo; Asoh, Kohsuke; Furuichi, Noriyuki; Ito, Toshiya; Kawada, Hatsuo; Hara, Sousuke; Ohwada, Jun; Miyagi, Takuho; Kobayashi, Takamitsu; Takanashi, Koichi; Tsukaguchi, Toshiyuki; Sakamoto, Hiroshi; Tsukuda, Takuo; Oikawa, Nobuhiro

doi:10.1016/j.bmc.2011.12.021

Cited by 145 publications

(101 citation statements)

References 15 publications

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“…Japan was the first country to approve alectinib in patients with advanced ALK-rearranged NSCLC, based on the results of the phase I/II AF-001JP trial targeting patients with ALK+ NSCLC who had not previously been treated with crizotinib or other ALK inhibitors [42,43]. In the phase II trial, 46 patients were treated and 43 of them (93.5 %) achieved an ORR (95 % CI 82.1-98.6).…”

Section: Alectinibmentioning

confidence: 99%

Tyrosine kinase inhibitors: new molecules in non-small cell lung cancer (EGFR AND ALK)

et al. 2017

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Section: Alectinibmentioning

confidence: 99%

Tyrosine kinase inhibitors: new molecules in non-small cell lung cancer (EGFR AND ALK)

et al. 2017

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“…[20] One of the inhibitors in development is Alectinib (RO5424802/CH5424802), designed by Roche to be more selective and potent at ALK inhibition than crizotinib. [25,26] Alectinib also has a selective activity against LTK and cyclin-G-associated kinase. However, unlike ceritinib, it is not active against IGF-1R and INSR.…”

Section: Next-generation Alk Tkismentioning

confidence: 99%

Overcoming crizotinib resistance in ALK-rearranged NSCLC with the second-generation ALK-inhibitor ceritinib

Muller

Langen

Honeywell

et al. 2016

Expert Review of Anticancer Therapy

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In up to 5% of non-small cell lung cancer (NSCLC) patients, the EML4-ALK translocation drives tumor progression. Treatment with the ALK inhibitor crizotinib is more effective than standard chemotherapy. However, resistance to crizotinib occurs after approximately 8 months. Ceritinib is the first second-generation ALK inhibitor approved for treatment of crizotinib-resistant NSCLC. Ceritinib inhibits two of the most common ALK-mutants that confer resistance to crizotinib: L1196 M and G1269A. Cells with ALK expression are more sensitive to ceritinib than crizotinib (IC 50 25 nM vs. 150 nM, respectively). Alternative second-generation ALK inhibitors such as Alectinib, Brigatinib and PF-06463922 are currently in development, each affecting different crizotinib-resistant ALK target mutations. Genetic identification of crizotinib-resistant mutants is essential for selecting the optimal treatment strategy in NSCLC patients to overcome resistance and to increase progression-free survival.ARTICLE HISTORY

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“…The medication was discontinued in 2 to 9 % of patients due to adverse events [148][149][150]. [152]. However, recently, it was discovered that alectinib potently inhibits RET kinase activity with an IC 50 of 4.8 nM, and is active against oncogenic RET-rearrangements observed in NSCLC [153].…”

Section: Clinical Safetymentioning

confidence: 99%

Tyrosine kinase inhibitors for EGFR- and ALK-mutated non-small cell lung cancer

Thompson

Menon

2016

ADMET DMPK

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Discovery of the epidermal growth receptor (EGFR) activating mutations and anaplastic lymphoma kinase (ALK) rearrangements has expanded the therapeutic landscape in non-small cell lung cancer (NSCLC). Survival outcomes for patients with these mutations have improved dramatically with EGFR and ALK tyrosine kinase inhibitors (TKIs). Multiple generations of EGFR and ALK TKIs have been rapidly developed, and patients and clinicians now have several options for first-and second-line treatments. While these small molecule

show abstract

Design and synthesis of a highly selective, orally active and potent anaplastic lymphoma kinase inhibitor (CH5424802)

Cited by 145 publications

References 15 publications

Tyrosine kinase inhibitors: new molecules in non-small cell lung cancer (EGFR AND ALK)

Tyrosine kinase inhibitors: new molecules in non-small cell lung cancer (EGFR AND ALK)

Overcoming crizotinib resistance in ALK-rearranged NSCLC with the second-generation ALK-inhibitor ceritinib

Tyrosine kinase inhibitors for EGFR- and ALK-mutated non-small cell lung cancer

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