Author(s): Agnieszka Dreas, Maciej Mikulski, Mariusz Milik, Charles-Henry Fabritius, Krzysztof Brzózka and Tomasz Rzymski*
Page: [3025 - 3053] Pages: 29
* (Excluding Mailing and Handling)
MAP kinase-interacting kinases (MNK1 and MNK2) are often activated downstream of ERK and p38 MAPK in the MAP kinase family. The role of MNKs in the development and progression of solid tumors and hematological malignancies has been widely discussed, particularly in the context of cap dependent translation, regulated by phosphorylation of eIF4E. MNK/eIF4E axis is involved in the expression of pro angiogenic, antiapoptotic, cell cycle, and motility proteins, such as MCL1, VEGF, MMP3, SNAIL, SMAD2, β-catenin or cyclin D1, and is essential during Ras and c Myc-induced transformation. MNK1/2 emerged as eligible targets for drug discovery in oncology, based on the antitumor effects observed in genetic knockout and RNA interference experiments and at the same time lack of adverse effects in dual knockout animals.
There is a high interest in the development of pharmacological inhibitors of MNK1/2 as not only tools for further basic research studies but also potential drugs in diseases characterized by deregulated translation. Unfortunately, the role of MNK1/2 in cancer still remains elusive due to the absence of potent and selective probes. Moreover, in many instances, hypotheses have been built reliant upon unspecific MNK1/2 inhibitors such as CGP57380 or cercosporamide. Lately, the first two clinical programs targeting MNKs in oncology have been revealed (eFT508 and BAY 1143269), although several other MNK programs are currently running at the preclinical stage. This review aims to provide an overview of recent progress in the development of MNK inhibitors.
Keywords: Protein kinase, kinase inhibitors, drug discovery, MNK1 MNK2, cancer, small molecule, eIF4E phosphorylation.
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CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"article" as access_level, j.issue_id, j.article_id from `user_access_article_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59829541 and j.to_ip >=59829541 )) and ((j.from_date <= 1736279941 and j.to_date >= 1736279941 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 81486)
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select * from `article` where `first_page` < '3025' and is_uploaded = 1 and issue_id = 7910 order by cast(first_page as SIGNED) desc limit 1
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select * from `article` where `last_page` > '3053' and is_uploaded = 1 and issue_id = 7910 order by cast(first_page as SIGNED) asc limit 1
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select `language_id` from `multilanguage` where `short_code` = 'en'
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select `source_lang_label`, `target_lang_label` from `multilanguage_labels` where `target_lang_id` = 1
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select `id` from `multilanguage_article` where `article_id` = 81486 limit 1
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select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` inner join `journal` as `j` on `j`.`journal_id` = `bd`.`content_id` where `b`.`banner_journal` = 1 and `bd`.`content_type` = 'J' and `bd`.`content_id` = 25 and `b`.`banner_from_date` <= 1736279941 and `b`.`banner_to_date` >= 1736279941 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
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select count(*) as aggregate from `uc_cart_products` where cart_id='02306497f6dee3e0a36e9589a078319f'
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|
200
[]
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