Anaplastic lymphoma kinase inhibitors as anticancer therapeutics: a patent review

Mesaros, Eugen F.; Ott, Gregory R.; Dorsey, Bruce D.

doi:10.1517/13543776.2014.877890

Cited by 28 publications

(13 citation statements)

References 61 publications

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“…This signaling pathway has a role in modulating mitosis, migration, and survival in cancer cells. [ 188 303 ] Expression of MET has been shown to be associated with a worse clinical outcome in GB. [ 11 157 158 176 ] GB expressing MET mutations or amplifications occur in only ~ 5% of all patients.…”

Section: Glioblastomamentioning

confidence: 99%

The future of high-grade glioma: Where we are and where are we going

Rhun¹,

Taillibert²,

Chamberlain³

2015

Surg Neurol Int

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High-grade glioma (HGG) are optimally treated with maximum safe surgery, followed by radiotherapy (RT) and/or systemic chemotherapy (CT). Recently, the treatment of newly diagnosed anaplastic glioma (AG) has changed, particularly in patients with 1p19q codeleted tumors. Results of trials currenlty ongoing are likely to determine the best standard of care for patients with noncodeleted AG tumors. Trials in AG illustrate the importance of molecular characterization, which are germane to both prognosis and treatment. In contrast, efforts to improve the current standard of care of newly diagnosed glioblastoma (GB) with, for example, the addition of bevacizumab (BEV), have been largely disappointing and furthermore molecular characterization has not changed therapy except in elderly patients. Novel approaches, such as vaccine-based immunotherapy, for newly diagnosed GB are currently being pursued in multiple clinical trials. Recurrent disease, an event inevitable in nearly all patients with HGG, continues to be a challenge. Both recurrent GB and AG are managed in similar manner and when feasible re-resection is often suggested notwithstanding limited data to suggest benefit from repeat surgery. Occassional patients may be candidates for re-irradiation but again there is a paucity of data to commend this therapy and only a minority of selected patients are eligible for this approach. Consequently systemic therapy continues to be the most often utilized treatment in recurrent HGG. Choice of therapy, however, varies and revolves around re-challenge with temozolomide (TMZ), use of a nitrosourea (most often lomustine; CCNU) or BEV, the most frequently used angiogenic inhibitor. Nevertheless, no clear standard recommendation regarding the prefered agent or combination of agents is avaliable. Prognosis after progression of a HGG remains poor, with an unmet need to improve therapy.

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Section: Glioblastomamentioning

confidence: 99%

The future of high-grade glioma: Where we are and where are we going

Rhun¹,

Taillibert²,

Chamberlain³

2015

Surg Neurol Int

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“…Among these, Ceritinib and Alectinib have The second-in-class ALK inhibitor 2,4-diaminopyrimidine Ceritinib (3) [25,26] and the third-in-class ALK inhibitor benzo [b]carbazolone Alectinib (5) [28][29][30] represent the two major chemotypes of second-generation ALK inhibitors possessing distinct structural characteristics. Compared to many medicinal chemistry efforts on the 2,4-diaminopyrimidine scaffold (as in 3) [7,9], limited structural optimization on the benzo[b]carbazolone scaffold (as in 5) has been reported, likely due to the difficulty in chemical synthesis. The currently available SAR on this tetracyclic framework was mostly reported by scientists at the Japanese company Chugai (a subsidiary of Roche) [28][29][30].…”

Section: <Insert Figure 1 Here>mentioning

confidence: 99%

“…Therefore, since the identification of EML4-ALK as a tumor oncogene in 2007, targeting EML4-ALK has been on the high-speed train as a novel MTT for the subclass of NSCLC patients, for whom currently available treatments are poorly effective [5][6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Novel tetracyclic benzo[b]carbazolones as highly potent and orally bioavailable ALK inhibitors: Design, synthesis, and structure—activity relationship study

Jiang

Zhou

et al. 2015

European Journal of Medicinal Chemistry

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“…During the past decade, the notion of directly targeting ALK has generated great research interest, with a host of groups discovering potent small-molecule ALK inhibitors [8]. However, arguably the most striking discovery in this field has been that of the small molecule crizotinib (Fig.…”

Section: Introductionmentioning

confidence: 99%

Computationally unraveling how ceritinib overcomes drug-resistance mutations in ALK-rearranged lung cancer

Zhang

2015

J Mol Model

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Anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase, has been implicated in the pathogenesis of several cancers. The small molecule ceritinib can overcome drug-resistance mutations that are observed in crizotinib-resistant patients, although the detailed mechanism for this ability of ceritinib remains elusive. Here, molecular dynamics (MD) simulations of six systems (including the apo ALK, the wild-type ALK-ceritinib complex, as well as four complexes of ceritinib with the I1171T, L1196M, S1206Y, and G1269A mutants of ALK, respectively) together with the subsequent molecular mechanics-generalized Born/surface area binding free energy calculations were performed to answer this question. Principal component analysis and domain cross-correlation analysis of MD trajectories revealed that ceritinib binding stabilized the conformational dynamics of both the wild-type and the four mutated ALKs as compared to the apo ALK. Moreover, the mutations had subtle effects on the conformation of ALK compared to that of the wild-type ALK. Importantly, binding free energy calculations demonstrated that, compared its effect on the wild-type ALK, ceritinib showed slightly increased potency towards the I1171T, L1196M, S1206Y, and G1269A mutants. Therefore, the binding of ceritinib to the four mutants can overcome crizotinib-resistant mutations. These data provide a structural and energetic explanation of how ceritinib overcomes mutation-induced drug resistance.

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Anaplastic lymphoma kinase inhibitors as anticancer therapeutics: a patent review

Cited by 28 publications

References 61 publications

The future of high-grade glioma: Where we are and where are we going

The future of high-grade glioma: Where we are and where are we going

Novel tetracyclic benzo[b]carbazolones as highly potent and orally bioavailable ALK inhibitors: Design, synthesis, and structure—activity relationship study

Computationally unraveling how ceritinib overcomes drug-resistance mutations in ALK-rearranged lung cancer

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