FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2067179863> ?p ?o ?g. }

• W2067179863 abstract "Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, ILThe RAS-dependent MAP kinase signaling pathway plays an important role in the regulation of cell proliferation and survival. RAS genes are frequently mutated in human cancer; however, it has not been possible to date to design direct inhibitors of RAS proteins. Inhibitors of the downstream kinase MEK are active against a subset of KRAS-mutant cancers in preclinical studies, but have shown limited success to date in clinical trials. We have identified a compound that potently inhibits MEK as well as Aurora kinases, a family of serine/threonine kinases involved in the regulation of mitosis. In enzymatic assays, BI 847325 inhibited the activity of Aurora A, B and C with IC50 values of 3, 25 and 15 nM, respectively; IC50 values of 25 and 4 nM were determined for MEK1 and MEK2, respectively. To determine whether the enzyme profile translates into cellular activity we used Western blot and FACE-ELISA assays of phospho-histone H3 (pHH3) and phospho-ERK (pERK) levels in cells treated with BI 847325 and observed EC50 values of 44 nM (NCI-H460 cells, KRAS and PI3Kα mutant) and 37 nM (A375 cells, BRAF mutant), respectively. In vitro profiling in a panel of 240 cell lines with diverse tissue origin and genetic background demonstrated that BI 847325 is a potent inhibitor of cell proliferation (gm GI50 = 28 nM) and induces cell death in a subset of cell lines. In vitro potency significantly correlated with mutations in RAS or BRAF. For comparison, a significant correlation of mutation status and sensitivity was also observed for a selective MEK inhibitor, AZD6244, but not for a selective Aurora inhibitor, BI 811283. In vivo efficacy was studied in nude mouse xenograft models of NSCLC (Calu-6, mutant KRAS) and cutaneous melanoma (A375, mutant BRAF). A daily oral dose of 10 mg/kg resulted in complete inhibition of tumor growth in the Calu-6 model (TGI = 102%, regression in 4/7 animals) and the A375 model (TGI = 116%, regression in 7/7 animals). Inhibition of Aurora B and MEK was monitored ex vivo by determining the phosphorylation state of histone H3 and ERK1/2 in tumor tissue. Immunohistochemical analyses confirmed a significant reduction of both pERK and pHH3 levels in the A375 tumors of treated animals compared to controls. To further profile the mode of action of the compound, the efficacy of BI 847325 in the MIAPaCa2-pancreatic adenocarcinoma model (mutant KRAS) was directly compared with that of the MEK inhibitor GSK 1120212. BI 847325 effectively induced tumor regression (TGI on day 22 = 126%) that was maintained in all animals on day 43. In contrast, treatment with GSK 112021 resulted in initial tumor regression, followed by re-growth after 3-4 weeks (TGI on day 22 = 129%; regrowth on day 43 in 5/7 animals). Inhibition of Aurora kinase in addition to MEK blockade thus may prevent/delay onset of resistance. Additional xenograft models with diverse genetic background are currently under investigation. Clinical development of BI 847325 has been initiated.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1919. doi:1538-7445.AM2012-1919" @default.
• W2067179863 created "2016-06-24" @default.
• W2067179863 creator A5011186689 @default.
• W2067179863 creator A5011521400 @default.
• W2067179863 creator A5018142249 @default.
• W2067179863 creator A5020933606 @default.
• W2067179863 creator A5023344154 @default.
• W2067179863 creator A5027198896 @default.
• W2067179863 creator A5041917353 @default.
• W2067179863 creator A5045554885 @default.
• W2067179863 creator A5065339919 @default.
• W2067179863 creator A5070801716 @default.
• W2067179863 creator A5075032820 @default.
• W2067179863 date "2012-04-15" @default.
• W2067179863 modified "2023-09-25" @default.
• W2067179863 title "Abstract 1919: Pharmacological characterization of BI 847325, a dual inhibitor of MEK and Aurora kinases" @default.
• W2067179863 doi "https://doi.org/10.1158/1538-7445.am2012-1919" @default.
• W2067179863 hasPublicationYear "2012" @default.
• W2067179863 type Work @default.
• W2067179863 sameAs 2067179863 @default.
• W2067179863 citedByCount "1" @default.
• W2067179863 countsByYear W20671798632015 @default.
• W2067179863 crossrefType "proceedings-article" @default.
• W2067179863 hasAuthorship W2067179863A5011186689 @default.
• W2067179863 hasAuthorship W2067179863A5011521400 @default.
• W2067179863 hasAuthorship W2067179863A5018142249 @default.
• W2067179863 hasAuthorship W2067179863A5020933606 @default.
• W2067179863 hasAuthorship W2067179863A5023344154 @default.
• W2067179863 hasAuthorship W2067179863A5027198896 @default.
• W2067179863 hasAuthorship W2067179863A5041917353 @default.
• W2067179863 hasAuthorship W2067179863A5045554885 @default.
• W2067179863 hasAuthorship W2067179863A5065339919 @default.
• W2067179863 hasAuthorship W2067179863A5070801716 @default.
• W2067179863 hasAuthorship W2067179863A5075032820 @default.
• W2067179863 hasConcept C104317684 @default.
• W2067179863 hasConcept C121608353 @default.
• W2067179863 hasConcept C153911025 @default.
• W2067179863 hasConcept C184235292 @default.
• W2067179863 hasConcept C20552341 @default.
• W2067179863 hasConcept C2781187634 @default.
• W2067179863 hasConcept C29537977 @default.
• W2067179863 hasConcept C501734568 @default.
• W2067179863 hasConcept C502942594 @default.
• W2067179863 hasConcept C54355233 @default.
• W2067179863 hasConcept C55493867 @default.
• W2067179863 hasConcept C57074206 @default.
• W2067179863 hasConcept C62112901 @default.
• W2067179863 hasConcept C62478195 @default.
• W2067179863 hasConcept C86554907 @default.
• W2067179863 hasConcept C86803240 @default.
• W2067179863 hasConcept C93304396 @default.
• W2067179863 hasConcept C95444343 @default.
• W2067179863 hasConceptScore W2067179863C104317684 @default.
• W2067179863 hasConceptScore W2067179863C121608353 @default.
• W2067179863 hasConceptScore W2067179863C153911025 @default.
• W2067179863 hasConceptScore W2067179863C184235292 @default.
• W2067179863 hasConceptScore W2067179863C20552341 @default.
• W2067179863 hasConceptScore W2067179863C2781187634 @default.
• W2067179863 hasConceptScore W2067179863C29537977 @default.
• W2067179863 hasConceptScore W2067179863C501734568 @default.
• W2067179863 hasConceptScore W2067179863C502942594 @default.
• W2067179863 hasConceptScore W2067179863C54355233 @default.
• W2067179863 hasConceptScore W2067179863C55493867 @default.
• W2067179863 hasConceptScore W2067179863C57074206 @default.
• W2067179863 hasConceptScore W2067179863C62112901 @default.
• W2067179863 hasConceptScore W2067179863C62478195 @default.
• W2067179863 hasConceptScore W2067179863C86554907 @default.
• W2067179863 hasConceptScore W2067179863C86803240 @default.
• W2067179863 hasConceptScore W2067179863C93304396 @default.
• W2067179863 hasConceptScore W2067179863C95444343 @default.
• W2067179863 hasLocation W20671798631 @default.
• W2067179863 hasOpenAccess W2067179863 @default.
• W2067179863 hasPrimaryLocation W20671798631 @default.
• W2067179863 hasRelatedWork W1417458945 @default.
• W2067179863 hasRelatedWork W1546835108 @default.
• W2067179863 hasRelatedWork W1983837434 @default.
• W2067179863 hasRelatedWork W1983915589 @default.
• W2067179863 hasRelatedWork W2079860615 @default.
• W2067179863 hasRelatedWork W2089553218 @default.
• W2067179863 hasRelatedWork W2099516828 @default.
• W2067179863 hasRelatedWork W2111281816 @default.
• W2067179863 hasRelatedWork W2169278779 @default.
• W2067179863 hasRelatedWork W2276670880 @default.
• W2067179863 hasRelatedWork W2312666898 @default.
• W2067179863 hasRelatedWork W2313737236 @default.
• W2067179863 hasRelatedWork W2326902209 @default.
• W2067179863 hasRelatedWork W2497243288 @default.
• W2067179863 hasRelatedWork W2562473065 @default.
• W2067179863 hasRelatedWork W2566260774 @default.
• W2067179863 hasRelatedWork W2619254438 @default.
• W2067179863 hasRelatedWork W2886350117 @default.
• W2067179863 hasRelatedWork W2980191829 @default.
• W2067179863 hasRelatedWork W3082285006 @default.
• W2067179863 isParatext "false" @default.
• W2067179863 isRetracted "false" @default.
• W2067179863 magId "2067179863" @default.
• W2067179863 workType "article" @default.