FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2086113883> ?p ?o ?g. }

• W2086113883 abstract "The family of cyclin-dependent kinase (CDK) proteins consists of multiple cell cycle regulating CDK members as well as members involved in the regulation of gene transcription like CDK9/PTEFb (positive transcription elongation factor b). Inhibition of PTEFb and its direct downstream target RNA polymerase II is thought to cause rapid depletion of short-lived mRNA transcripts of important survival proteins like c-myc and Mcl-1 and thereby to induce growth delay and apoptosis in addicted tumor cells. In contrast to pan-CDK inhibitiors which are currently evaluated in Phase I and II clinical trials, PTEFb selective inhibitors have not been explored for clinical utility. BAY 1112054 is a potent and highly selective PTEFb-kinase inhibitor with low nanomolar activity against PTEFb/CDK9 and an at least 50-fold selectivity against other CDKs in enzymatic assays. Furthermore, BAY 1112054 shows a favourable selectivity against non-CDK kinases in vitro. The compound exhibits broad anti-proliferative activity against a panel of tumor cell lines with sub-micromolar IC-50 values. In line with the proposed mode of action, a concentration-dependent inhibition of the phosphorylation of the RNA polymerase II was observed in A549 tumor cells. This inhibition was accompanied by a reduction of intracellular Mcl-1 protein levels. Furthermore, BAY 1112054 increased DNA fragmentation in synchronized HeLa cells upon compound treatment for 24 hours. BAY 1112054 showed convincing in vivo efficacy at tolerated doses in two xenograft models in mice. Once daily oral treatment led to complete tumor stasis in established MOLM-13 AML xenografts. Pharmacokinetic analysis revealed that unbound plasma levels were 8 to 12 hours above the cellular IC50 in this model. In vivo efficacy and tolerability of the once daily po schedule of BAY 1112054 was confirmed in NCI-H82 SCLC xenografts. Xenografted tumors of this model showed lower levels of RNA polymerase II phosphorylation and Mcl-1 upon treatment with BAY 1112054. In conclusion, our data provides in vitro and in vivo proof of concept for BAY 1112054, a potent and highly selective inhibitor of PTEFb/CDK9 with first-in-class potential, and warrant further clinical evaluation of PTEFb selective inhibitors for the treatment of cancers addicted to the transcription of short-lived anti-apoptotic survival proteins. Citation Format: Arne Scholz, Ulrich Lucking, Gerhard Siemeister, Philip Lienau, Knut Eis, Antje Wengner, Kirstin Petersen, Ulf Bomer, Peter Nussbaumer, Axel Choidas, Gerd Ruhter, Jan Eickhoff, Carsten Schultz-Fademrecht, Bert Klebl, Stuart Ince, Franz von Nussbaum, Dominik Mumberg, Michael Brands, Karl Ziegelbauer. BAY 1112054, a highly selective, potent and orally available inhibitor of PTEFb/CDK9, shows convincing anti-tumor activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4538. doi:10.1158/1538-7445.AM2014-4538" @default.
• W2086113883 created "2016-06-24" @default.
• W2086113883 creator A5000171859 @default.
• W2086113883 creator A5009093201 @default.
• W2086113883 creator A5009359386 @default.
• W2086113883 creator A5021915190 @default.
• W2086113883 creator A5030057178 @default.
• W2086113883 creator A5031155849 @default.
• W2086113883 creator A5040107084 @default.
• W2086113883 creator A5044740532 @default.
• W2086113883 creator A5051451842 @default.
• W2086113883 creator A5052263137 @default.
• W2086113883 creator A5064749364 @default.
• W2086113883 creator A5064950429 @default.
• W2086113883 creator A5073811144 @default.
• W2086113883 creator A5076418694 @default.
• W2086113883 creator A5077558723 @default.
• W2086113883 creator A5084853335 @default.
• W2086113883 creator A5086564468 @default.
• W2086113883 creator A5088384184 @default.
• W2086113883 creator A5090413812 @default.
• W2086113883 date "2014-09-30" @default.
• W2086113883 modified "2023-09-26" @default.
• W2086113883 title "Abstract 4538: BAY 1112054, a highly selective, potent and orally available inhibitor of PTEFb/CDK9, shows convincing anti-tumor activity" @default.
• W2086113883 doi "https://doi.org/10.1158/1538-7445.am2014-4538" @default.
• W2086113883 hasPublicationYear "2014" @default.
• W2086113883 type Work @default.
• W2086113883 sameAs 2086113883 @default.
• W2086113883 citedByCount "1" @default.
• W2086113883 countsByYear W20861138832016 @default.
• W2086113883 crossrefType "proceedings-article" @default.
• W2086113883 hasAuthorship W2086113883A5000171859 @default.
• W2086113883 hasAuthorship W2086113883A5009093201 @default.
• W2086113883 hasAuthorship W2086113883A5009359386 @default.
• W2086113883 hasAuthorship W2086113883A5021915190 @default.
• W2086113883 hasAuthorship W2086113883A5030057178 @default.
• W2086113883 hasAuthorship W2086113883A5031155849 @default.
• W2086113883 hasAuthorship W2086113883A5040107084 @default.
• W2086113883 hasAuthorship W2086113883A5044740532 @default.
• W2086113883 hasAuthorship W2086113883A5051451842 @default.
• W2086113883 hasAuthorship W2086113883A5052263137 @default.
• W2086113883 hasAuthorship W2086113883A5064749364 @default.
• W2086113883 hasAuthorship W2086113883A5064950429 @default.
• W2086113883 hasAuthorship W2086113883A5073811144 @default.
• W2086113883 hasAuthorship W2086113883A5076418694 @default.
• W2086113883 hasAuthorship W2086113883A5077558723 @default.
• W2086113883 hasAuthorship W2086113883A5084853335 @default.
• W2086113883 hasAuthorship W2086113883A5086564468 @default.
• W2086113883 hasAuthorship W2086113883A5088384184 @default.
• W2086113883 hasAuthorship W2086113883A5090413812 @default.
• W2086113883 hasConcept C101762097 @default.
• W2086113883 hasConcept C104317684 @default.
• W2086113883 hasConcept C124320809 @default.
• W2086113883 hasConcept C138885662 @default.
• W2086113883 hasConcept C1491633281 @default.
• W2086113883 hasConcept C150194340 @default.
• W2086113883 hasConcept C153911025 @default.
• W2086113883 hasConcept C179926584 @default.
• W2086113883 hasConcept C184235292 @default.
• W2086113883 hasConcept C185592680 @default.
• W2086113883 hasConcept C190283241 @default.
• W2086113883 hasConcept C2777366897 @default.
• W2086113883 hasConcept C2778298596 @default.
• W2086113883 hasConcept C29537977 @default.
• W2086113883 hasConcept C41895202 @default.
• W2086113883 hasConcept C502942594 @default.
• W2086113883 hasConcept C55493867 @default.
• W2086113883 hasConcept C64350747 @default.
• W2086113883 hasConcept C86803240 @default.
• W2086113883 hasConcept C95444343 @default.
• W2086113883 hasConceptScore W2086113883C101762097 @default.
• W2086113883 hasConceptScore W2086113883C104317684 @default.
• W2086113883 hasConceptScore W2086113883C124320809 @default.
• W2086113883 hasConceptScore W2086113883C138885662 @default.
• W2086113883 hasConceptScore W2086113883C1491633281 @default.
• W2086113883 hasConceptScore W2086113883C150194340 @default.
• W2086113883 hasConceptScore W2086113883C153911025 @default.
• W2086113883 hasConceptScore W2086113883C179926584 @default.
• W2086113883 hasConceptScore W2086113883C184235292 @default.
• W2086113883 hasConceptScore W2086113883C185592680 @default.
• W2086113883 hasConceptScore W2086113883C190283241 @default.
• W2086113883 hasConceptScore W2086113883C2777366897 @default.
• W2086113883 hasConceptScore W2086113883C2778298596 @default.
• W2086113883 hasConceptScore W2086113883C29537977 @default.
• W2086113883 hasConceptScore W2086113883C41895202 @default.
• W2086113883 hasConceptScore W2086113883C502942594 @default.
• W2086113883 hasConceptScore W2086113883C55493867 @default.
• W2086113883 hasConceptScore W2086113883C64350747 @default.
• W2086113883 hasConceptScore W2086113883C86803240 @default.
• W2086113883 hasConceptScore W2086113883C95444343 @default.
• W2086113883 hasLocation W20861138831 @default.
• W2086113883 hasOpenAccess W2086113883 @default.
• W2086113883 hasPrimaryLocation W20861138831 @default.
• W2086113883 hasRelatedWork W2012978731 @default.
• W2086113883 hasRelatedWork W2019465092 @default.
• W2086113883 hasRelatedWork W2026421486 @default.
• W2086113883 hasRelatedWork W2033787418 @default.
• W2086113883 hasRelatedWork W2035803637 @default.
• W2086113883 hasRelatedWork W2043426015 @default.
• W2086113883 hasRelatedWork W2065395067 @default.

• next