Matches in SemOpenAlex for { <https://semopenalex.org/work/W1576752489> ?p ?o ?g. }
Showing items 1 to 89 of
89
with 100 items per page.
- W1576752489 endingPage "1140" @default.
- W1576752489 startingPage "1139" @default.
- W1576752489 abstract "4853 The Stat3 pathway, constitutively activated in many cancers, is associated with the regulation of many survival proteins including survivin, Mcl-1, and the Bcl family. Inhibition of Stat3 signaling leads to an inhibition of cancer cell growth and to the induction of apoptosis. A number of attempts have been made to abrogate Stat3 activity, including the use of ligands to inhibit upstream signaling events or silencing Stat3 with oligonucleotides, none of which have been successful in vivo. We report here on the first potent small molecule inhibitor of Stat3 with demonstrated in vivo activity. Studies of WP1066 in our laboratories demonstrated proapoptotic and antiproliferative activity at concentrations of 3-5 μM, in vitro, in a variety of tumor cell types. In order to determine the utility of this compound in vivo we examined the tissue stability, pharmacokinetics, drug distribution, and bioavailability in CD1 mice. Briefly, animals (10 per timepoint) were administered WP1066 (10 and 40 mg/kg) as an IV bolus and sacrificed at various out to 24 hours post-dose. Tissues were harvested and following extraction analyzed for WP1066 content using tandem LC/MS. In vitro studies were also conducted to determine the overall stability of this molecule in rodent plasma. For oral bioavailability studies animals were dosed by gavage with 40 mg/kg and samples obtained over the same 24 hour period. The mean achieved peak plasma concentrations following 10 and 40 mg/kg IV doses were 1.05 and 4.31 μM respectively. Mean drug half life was 4.5 hours and terminal concentrations measured at 12 and 18 hours were 0.03 and 0.13 μM, at the low and high doses, respectively. Tissue stability studies demonstrated an in vitro plasma half-life of 2.6 hrs. Preliminary oral bioavailability studies yielded mean peak plasma concentrations of > 1 μM and an estimated bioavailability of 0.2. Studies of U87 tumor bearing mice given drug by IV bolus demonstrated an accumulation of WP1066 in tumor tissue many fold greater than the simultaneously measured plasma concentration. These studies coupled with our in vivo efficacy studies indicate that WP1066 is the first small molecule inhibitor of Stat3 capable of achieving and maintaining tissue concentrations associated with drug activity in vivo." @default.
- W1576752489 created "2016-06-24" @default.
- W1576752489 creator A5016121227 @default.
- W1576752489 creator A5020590699 @default.
- W1576752489 creator A5049265932 @default.
- W1576752489 creator A5050861848 @default.
- W1576752489 creator A5052796693 @default.
- W1576752489 creator A5061032146 @default.
- W1576752489 creator A5062959791 @default.
- W1576752489 creator A5086839893 @default.
- W1576752489 creator A5091853246 @default.
- W1576752489 date "2006-04-15" @default.
- W1576752489 modified "2023-09-27" @default.
- W1576752489 title "The preclinical pharmacology of WP1066, a potent small molecule inhibitor of the JAK2/STAT3 pathway" @default.
- W1576752489 hasPublicationYear "2006" @default.
- W1576752489 type Work @default.
- W1576752489 sameAs 1576752489 @default.
- W1576752489 citedByCount "2" @default.
- W1576752489 countsByYear W15767524892013 @default.
- W1576752489 crossrefType "journal-article" @default.
- W1576752489 hasAuthorship W1576752489A5016121227 @default.
- W1576752489 hasAuthorship W1576752489A5020590699 @default.
- W1576752489 hasAuthorship W1576752489A5049265932 @default.
- W1576752489 hasAuthorship W1576752489A5050861848 @default.
- W1576752489 hasAuthorship W1576752489A5052796693 @default.
- W1576752489 hasAuthorship W1576752489A5061032146 @default.
- W1576752489 hasAuthorship W1576752489A5062959791 @default.
- W1576752489 hasAuthorship W1576752489A5086839893 @default.
- W1576752489 hasAuthorship W1576752489A5091853246 @default.
- W1576752489 hasConcept C112705442 @default.
- W1576752489 hasConcept C150903083 @default.
- W1576752489 hasConcept C181389837 @default.
- W1576752489 hasConcept C185592680 @default.
- W1576752489 hasConcept C190283241 @default.
- W1576752489 hasConcept C202751555 @default.
- W1576752489 hasConcept C207001950 @default.
- W1576752489 hasConcept C2775975398 @default.
- W1576752489 hasConcept C2777408456 @default.
- W1576752489 hasConcept C2778923194 @default.
- W1576752489 hasConcept C31573885 @default.
- W1576752489 hasConcept C55493867 @default.
- W1576752489 hasConcept C71924100 @default.
- W1576752489 hasConcept C86803240 @default.
- W1576752489 hasConcept C98274493 @default.
- W1576752489 hasConceptScore W1576752489C112705442 @default.
- W1576752489 hasConceptScore W1576752489C150903083 @default.
- W1576752489 hasConceptScore W1576752489C181389837 @default.
- W1576752489 hasConceptScore W1576752489C185592680 @default.
- W1576752489 hasConceptScore W1576752489C190283241 @default.
- W1576752489 hasConceptScore W1576752489C202751555 @default.
- W1576752489 hasConceptScore W1576752489C207001950 @default.
- W1576752489 hasConceptScore W1576752489C2775975398 @default.
- W1576752489 hasConceptScore W1576752489C2777408456 @default.
- W1576752489 hasConceptScore W1576752489C2778923194 @default.
- W1576752489 hasConceptScore W1576752489C31573885 @default.
- W1576752489 hasConceptScore W1576752489C55493867 @default.
- W1576752489 hasConceptScore W1576752489C71924100 @default.
- W1576752489 hasConceptScore W1576752489C86803240 @default.
- W1576752489 hasConceptScore W1576752489C98274493 @default.
- W1576752489 hasLocation W15767524891 @default.
- W1576752489 hasOpenAccess W1576752489 @default.
- W1576752489 hasPrimaryLocation W15767524891 @default.
- W1576752489 hasRelatedWork W1548640328 @default.
- W1576752489 hasRelatedWork W1909698616 @default.
- W1576752489 hasRelatedWork W1965462445 @default.
- W1576752489 hasRelatedWork W1967667262 @default.
- W1576752489 hasRelatedWork W1995429086 @default.
- W1576752489 hasRelatedWork W2015997206 @default.
- W1576752489 hasRelatedWork W2099180944 @default.
- W1576752489 hasRelatedWork W2102978104 @default.
- W1576752489 hasRelatedWork W2132922650 @default.
- W1576752489 hasRelatedWork W2138419309 @default.
- W1576752489 hasRelatedWork W2139356368 @default.
- W1576752489 hasRelatedWork W2150320812 @default.
- W1576752489 hasRelatedWork W2151513527 @default.
- W1576752489 hasRelatedWork W2168478794 @default.
- W1576752489 hasRelatedWork W2169820627 @default.
- W1576752489 hasRelatedWork W2766297112 @default.
- W1576752489 hasRelatedWork W2783142245 @default.
- W1576752489 hasRelatedWork W2918225842 @default.
- W1576752489 hasRelatedWork W2921785857 @default.
- W1576752489 hasRelatedWork W2972840897 @default.
- W1576752489 hasVolume "66" @default.
- W1576752489 isParatext "false" @default.
- W1576752489 isRetracted "false" @default.
- W1576752489 magId "1576752489" @default.
- W1576752489 workType "article" @default.