Discovery of (R,E)-N-(7-Chloro-1-(1-[4-(dimethylamino)but-2-enoyl]azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide (EGF816), a Novel, Potent, and WT Sparing Covalent Inhibitor of Oncogenic (L858R, ex19del) and Resistant (T790M) EGFR Mutants for the Treatment of EGFR Mutant Non-Small-Cell Lung Cancers

Lelais, Gérald; Epple, Robert; Marsilje, Thomas H.; Long, Yun Oliver; McNeill, Matthew; Chen, Bei; Lu, Wei; Anumolu, Jaganmohan; Badiger, Sangamesh E.; Bursulaya, Badry; DiDonato, Michael; Fong, Rina; Juarez, Jose; Li, Jie; Manuia, Mari; Mason, Daniel E.; Gordon, Perry; Groessl, Todd; Johnson, Kevin C.; Jia, Yong; Kasibhatla, Shailaja; Li, Chun; Isbell, John; Spraggon, Glen; Bender, Steven L.; Michellys, Pierre‐Yves

doi:10.1021/acs.jmedchem.5b01985

Cited by 86 publications

(57 citation statements)

References 46 publications

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“…Nazartinib is a novel, irreversible mutant-selective EGFR inhibitor that specifically targets both EGFR -activating mutations (L858R, Del19) and the resistant T790M mutation, while sparing wild-type EGFR (50). NCT02108964 (EGF816X2101) is a phase I/II first-in-human study of nazartinib in patients with EGFR -mutated locally advanced or metastatic NSCLC.…”

Section: Targeting Egfr T790m+ Nsclcmentioning

confidence: 99%

Next-Generation EGFR Tyrosine Kinase Inhibitors for Treating EGFR-Mutant Lung Cancer beyond First Line

Sullivan

Planchard

2017

Front. Med.

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Tyrosine kinase inhibitors (TKIs) against the human epidermal growth factor receptor (EGFR) are now standard treatment in the clinic for patients with advanced EGFR mutant non-small-cell lung cancer (NSCLC). First-generation EGFR TKIs, binding competitively and reversibly to the ATP-binding site of the EGFR tyrosine kinase domain, have resulted in a significant improvement in outcome for NSCLC patients with activating EGFR mutations (L858R and Del19). However, after a median duration of response of ~12 months, all patients develop tumor resistance, and in over half of these patients this is due to the emergence of the EGFR T790M resistance mutation. The second-generation EGFR/HER TKIs were developed to treat resistant disease, targeting not only T790M but EGFR-activating mutations and wild-type EGFR. Although they exhibited promising anti-T790M activity in the laboratory, their clinical activity among T790M+ NSCLC was poor mainly because of dose-limiting toxicity due to simultaneous inhibition of wild-type EGFR. The third-generation EGFR TKIs selectively and irreversibly target EGFR T790M and activating EGFR mutations, showing promising efficacy in NSCLC resistant to the first- and second-generation EGFR TKIs. They also appear to have lower incidences of toxicity due to the limited inhibitory effect on wild-type EGFR. Currently, the first-generation gefitinib and erlotinib and second-generation afatinib have been approved for first-line treatment of metastatic NSCLC with activating EGFR mutations. Among the third-generation EGFR TKIs, osimertinib is today the only drug approved by the Food and Drug Administration and the European Medicines Agency to treat metastatic EGFR T790M NSCLC patients who have progressed on or after EGFR TKI therapy. In this review, we summarize the available post-progression therapies including third-generation EGFR inhibitors and combination treatment strategies for treating patients with NSCLC harboring EGFR mutations and address the known mechanisms of resistance.

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Section: Targeting Egfr T790m+ Nsclcmentioning

confidence: 99%

Next-Generation EGFR Tyrosine Kinase Inhibitors for Treating EGFR-Mutant Lung Cancer beyond First Line

Sullivan

Planchard

2017

Front. Med.

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“…Pre-clinical data showed that nazartinib showed similar mutant-selectivity and EGFR wild-type sparing property similar to other third generation EGFR TKIs [25]. …”

Section: Introductionmentioning

confidence: 99%

Third generation EGFR TKIs: current data and future directions

et al. 2018

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Acquired T790 M mutation is the commonest cause of resistance for advanced non-small cell lung cancer (NSCLC) epidermal growth factor receptor (EGFR) mutant patients who had progressed after first line EGFR TKI (tyrosine kinase inhibitor). Several third generation EGFR TKIs which are EGFR mutant selective and wild-type (WT) sparing were developed to treat these patients with T790 M acquired resistant mutation. Osimertinib is one of the third generation EGFR TKIs and is currently the most advanced in clinical development. Unfortunately, despite good initial response, patients who was treated with third generation EGFR TKI would develop acquired resistance and several mechanisms had been identified and the commonest being C797S mutation at exon 20. Several novel treatment options were being developed for patients who had progressed on third generation EGFR TKI but they are still in the early phase of development. Osimertinib under FLAURA study had been shown to have better progression-free survival over first generation EGFR TKI in the first line setting and likely will become the new standard of care.

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“…Saldivia et al recently found that a covalent kinase inhibitor AB1 (Lelais et al, 2016) has potent activity against several trypanosomatids and identified KKT10 as a target in bloodstream form T. brucei (Saldivia et al, 2019). They also found that KKT10 phosphorylated KKT2 at serine 507 and/or serine 508 and that the KKT2 S507A S508A phosphodeficient mutant failed to rescue the growth defect caused by KKT2 RNAi in bloodstream form cells.…”

Section: Discussionmentioning

confidence: 99%

Unconventional kinetochore kinases KKT10/19 promote the metaphase to anaphase transition in Trypanosoma brucei

Ishii

Akiyoshi

2019

Preprint

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Trypanosoma brucei has unique kinetochore proteins and lacks a canonical spindle checkpoint system. How mitotic progression is regulated in this organism remains unclear.Here we show that two redundant protein kinases KKT10/19 promote the metaphase to anaphase transition. AbstractThe kinetochore is a macromolecular protein complex that drives chromosome segregation in eukaryotes. Unlike most eukaryotes that have canonical kinetochore proteins, evolutionarily divergent kinetoplastids such as Trypanosoma brucei have unconventional kinetochore proteins. T. brucei also lacks a canonical spindle checkpoint system and it therefore remains unknown how mitotic progression is regulated in this organism. Here we characterized two paralogous kinetochore proteins with a CLK-like kinase domain, KKT10 and KKT19, which localize at kinetochores in metaphase but disappear at the onset of anaphase. We found that these proteins are functionally redundant. Double knockdown of KKT10/19 led to a significant delay in the metaphase to anaphase transition. A kinase-dead mutant of KKT10 failed to rescue the KKT10/19 depletion phenotype, suggesting that its 2 kinase activity is essential. We also found that phosphorylation of two kinetochore proteins KKT4 and KKT7 depends on KKT10/19 in vivo. Finally, we showed that the N-terminal part of KKT7 directly interacts with KKT10 and that kinetochore localization of KKT10 depends not only on KKT7 but also on the KKT8 complex. Our results reveal that kinetochore localization of KKT10/19 is tightly controlled to regulate the metaphase to anaphase transition in T. brucei.

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Cited by 86 publications

References 46 publications

Next-Generation EGFR Tyrosine Kinase Inhibitors for Treating EGFR-Mutant Lung Cancer beyond First Line

Next-Generation EGFR Tyrosine Kinase Inhibitors for Treating EGFR-Mutant Lung Cancer beyond First Line

Third generation EGFR TKIs: current data and future directions

Unconventional kinetochore kinases KKT10/19 promote the metaphase to anaphase transition in Trypanosoma brucei

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