FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W1556562103> ?p ?o ?g. }

• W1556562103 endingPage "3297" @default.
• W1556562103 startingPage "3297" @default.
• W1556562103 abstract "AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA3297 The ribosome controls the rate of cell proliferation and eventually its fate. A central component of the ribosome is rRNA, which is synthesized in the nucleolus by RNA Polymerase I (Pol I). The synthesis of rRNA is initiated by the assembly of Pol I and a defined set of transcription factors to form the pre-initiation complex (PIC). Part of the PIC is the TBP-TAF assembly of proteins called SL1, and Pol I cannot function without it. Several known tumor-suppressors (p53, Rb, PTEN) that are often lost during tumorigenesis were shown to negatively effect the functioning of SL1 making it a lucrative target for oncology. Here we report a small molecule CX-5461 that selectively inhibits rRNA synthesis by interfering with SL1. As expected, with a compound that modulates ribosome biogenesis, CX-5461 demonstrated strong anti-proliferative potency against a broad range of tumor cell lines in vitro , and it has also shown potent oral activity in mouse xenograft models of human cancers. CX-5461 was tested for the inhibition of various human RNA Polymerases with a series of nuclear extract-based transcriptional assays and demonstrated good potency and selectivity for Pol I IC50 = 0.7 uM, versus Pol II (11 uM) and Pol III (4 uM). The potency and selectivity are also translated to cell culture. qRT-PCR analysis of total RNA from cells treated with CX-5461 showed that drug was more potent in depleting the pre-rRNA levels (IC50 = 0.25 uM) than RNA Polymerase II transcribed c-Myc mRNA levels (IC50 = 3.72 uM). The compounds mechanism of action studies based on ChiP assay showed that drug interfered with SL1 induced assembly of PIC. In Alamar Blue cell viability assays CX-5461 had an average IC50 against 20 varied cell lines from those of pancreas, prostate, colorectal, lung, breast, ovary etc of 78nM. In mouse xenograft model of human pancreatic cancer (Mia PaCa-2) CX-5461 demonstrated strong tumor reduction when given orally with T/C of 37% and insignificant weight loss. Selective inhibition of SL1 is effective in models of cancer and gives good efficacy with low side effects. Compound CX-5461 is an orally active small molecule that is in preclinical development as a broad spectrum antitumor agent." @default.
• W1556562103 created "2016-06-24" @default.
• W1556562103 creator A5003100815 @default.
• W1556562103 creator A5018485011 @default.
• W1556562103 creator A5021286275 @default.
• W1556562103 creator A5024503165 @default.
• W1556562103 creator A5043544496 @default.
• W1556562103 creator A5050272324 @default.
• W1556562103 creator A5067274113 @default.
• W1556562103 creator A5071536865 @default.
• W1556562103 creator A5084450353 @default.
• W1556562103 creator A5089576016 @default.
• W1556562103 date "2008-05-01" @default.
• W1556562103 modified "2023-09-22" @default.
• W1556562103 title "CX-5461 selectively inhibits the SL1 Component of RNA Polymerase I in the ribosome biogenesis pathway and gives potent antitumor activity in models of cancer" @default.
• W1556562103 hasPublicationYear "2008" @default.
• W1556562103 type Work @default.
• W1556562103 sameAs 1556562103 @default.
• W1556562103 citedByCount "0" @default.
• W1556562103 crossrefType "journal-article" @default.
• W1556562103 hasAuthorship W1556562103A5003100815 @default.
• W1556562103 hasAuthorship W1556562103A5018485011 @default.
• W1556562103 hasAuthorship W1556562103A5021286275 @default.
• W1556562103 hasAuthorship W1556562103A5024503165 @default.
• W1556562103 hasAuthorship W1556562103A5043544496 @default.
• W1556562103 hasAuthorship W1556562103A5050272324 @default.
• W1556562103 hasAuthorship W1556562103A5067274113 @default.
• W1556562103 hasAuthorship W1556562103A5071536865 @default.
• W1556562103 hasAuthorship W1556562103A5084450353 @default.
• W1556562103 hasAuthorship W1556562103A5089576016 @default.
• W1556562103 hasConcept C101762097 @default.
• W1556562103 hasConcept C104317684 @default.
• W1556562103 hasConcept C121608353 @default.
• W1556562103 hasConcept C138885662 @default.
• W1556562103 hasConcept C150194340 @default.
• W1556562103 hasConcept C153911025 @default.
• W1556562103 hasConcept C179926584 @default.
• W1556562103 hasConcept C183873130 @default.
• W1556562103 hasConcept C185592680 @default.
• W1556562103 hasConcept C190062978 @default.
• W1556562103 hasConcept C25281209 @default.
• W1556562103 hasConcept C2776449523 @default.
• W1556562103 hasConcept C2779419633 @default.
• W1556562103 hasConcept C41895202 @default.
• W1556562103 hasConcept C502942594 @default.
• W1556562103 hasConcept C54355233 @default.
• W1556562103 hasConcept C555283112 @default.
• W1556562103 hasConcept C64350747 @default.
• W1556562103 hasConcept C67705224 @default.
• W1556562103 hasConcept C67905577 @default.
• W1556562103 hasConcept C86803240 @default.
• W1556562103 hasConcept C88478588 @default.
• W1556562103 hasConceptScore W1556562103C101762097 @default.
• W1556562103 hasConceptScore W1556562103C104317684 @default.
• W1556562103 hasConceptScore W1556562103C121608353 @default.
• W1556562103 hasConceptScore W1556562103C138885662 @default.
• W1556562103 hasConceptScore W1556562103C150194340 @default.
• W1556562103 hasConceptScore W1556562103C153911025 @default.
• W1556562103 hasConceptScore W1556562103C179926584 @default.
• W1556562103 hasConceptScore W1556562103C183873130 @default.
• W1556562103 hasConceptScore W1556562103C185592680 @default.
• W1556562103 hasConceptScore W1556562103C190062978 @default.
• W1556562103 hasConceptScore W1556562103C25281209 @default.
• W1556562103 hasConceptScore W1556562103C2776449523 @default.
• W1556562103 hasConceptScore W1556562103C2779419633 @default.
• W1556562103 hasConceptScore W1556562103C41895202 @default.
• W1556562103 hasConceptScore W1556562103C502942594 @default.
• W1556562103 hasConceptScore W1556562103C54355233 @default.
• W1556562103 hasConceptScore W1556562103C555283112 @default.
• W1556562103 hasConceptScore W1556562103C64350747 @default.
• W1556562103 hasConceptScore W1556562103C67705224 @default.
• W1556562103 hasConceptScore W1556562103C67905577 @default.
• W1556562103 hasConceptScore W1556562103C86803240 @default.
• W1556562103 hasConceptScore W1556562103C88478588 @default.
• W1556562103 hasLocation W15565621031 @default.
• W1556562103 hasOpenAccess W1556562103 @default.
• W1556562103 hasPrimaryLocation W15565621031 @default.
• W1556562103 hasRelatedWork W135199364 @default.
• W1556562103 hasRelatedWork W1995597135 @default.
• W1556562103 hasRelatedWork W2005463558 @default.
• W1556562103 hasRelatedWork W2011390079 @default.
• W1556562103 hasRelatedWork W2015700471 @default.
• W1556562103 hasRelatedWork W2017847990 @default.
• W1556562103 hasRelatedWork W2022413799 @default.
• W1556562103 hasRelatedWork W2060405956 @default.
• W1556562103 hasRelatedWork W2066957238 @default.
• W1556562103 hasRelatedWork W2151744014 @default.
• W1556562103 hasRelatedWork W2154842546 @default.
• W1556562103 hasRelatedWork W2160195400 @default.
• W1556562103 hasRelatedWork W2161063957 @default.
• W1556562103 hasRelatedWork W2184802753 @default.
• W1556562103 hasRelatedWork W2194825305 @default.
• W1556562103 hasRelatedWork W2352039280 @default.
• W1556562103 hasRelatedWork W2371243258 @default.
• W1556562103 hasRelatedWork W3048893693 @default.
• W1556562103 hasRelatedWork W3206762147 @default.
• W1556562103 hasRelatedWork W2775069772 @default.
• W1556562103 hasVolume "68" @default.

• next