FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4296122547> ?p ?o ?g. }

• W4296122547 endingPage "A024" @default.
• W4296122547 startingPage "A024" @default.
• W4296122547 abstract "Abstract Introduction: Inhibition of poly-adenosine diphosphate-ribose polymerase (PARP) is an effective therapy against cancers with DNA damage repair (DDR) deficiencies, such as BRCA1 and BRCA2 defects. In preclinical studies, PARP inhibitors demonstrated potential therapeutic value in Ewing sarcoma (ES), though clinical trials with olaparib failed to show significant clinical benefit. While single agent therapy proved inefficacious in the clinical treatment of ES, combination therapies may show anti-tumour activity. A key regulatory event in DNA damage repair is acetylation and deacetylation of histones, controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Increased expression of HDACs have been correlated to more malignant phenotypes in sarcomas and inhibition of HDAC in ES has been shown to be effective in inhibiting tumor growth. HDAC inhibition combined with PARP inhibition has been shown to sensitize cells to treatment in vitro, however clinically, combination therapies often require sequential administration due to different pharmacokinetic profiles and overlapping toxicities, severely limiting clinical utility. Here, we evaluate the activity and efficacy of a novel bifunctional small-molecule compound designed to have both PARP and HDAC inhibiting activity. Methods: PARP1 activity was measured using the Trevigen Universal Colorimetric PARP Assay Kit and PARP2 activity was measured using the BPS Bioscience PARP2 Colorimetric PARP2 Assay Kit. HDAC activity was measured using HeLa nuclear extracts and a fluorogenic peptide-based biochemical assay. Cell survival EC50s were determined using live cell imaging with an Incucyte S3 system and the CellTiter Glo viability assay. Accumulation of phospho-histone H2AX (pH2AX) was detected by western blot using anti-phospho histone H2AX (Ser139) antibody from Cell Signaling Technologies. Results: A representative compound from the kt-3000 series showed potent inhibition of PARP1 and PARP2 with IC50 values in the low nM range, comparable to FDA-approved PARP inhibitors. The compound also showed inhibition of HDAC enzymes with IC50 values in the low µM range, slightly lower than the FDA-approved HDAC inhibitor, vorinostat. Cell survival EC50 values were superior to olaparib in ES cell lines in vitro. Treatment with the kt-3000 compound also resulted in the increased accumulation of pH2AX by western blot and increased S and G2/M cell cycle arrest compared to olaparib. Conclusion: Our kt-3000 compound shows potent inhibition of PARP1, PARP2, and HDAC, as well as induction of DNA damage and cell cycle arrest. Further development of these bifunctional single molecule inhibitors may result in a novel treatment opportunity for Ewing sarcoma. Citation Format: Sarah Truong, Beibei Zhai, Fariba Ghaidi, Louise Ramos, Jay Joshi, Dennis Brown, Neil Sankar, John Langlands, Jeffrey Bacha, Wang Shen, Poul Sorensen, Mads Daugaard. In vitro efficacy of a novel dual PARP-HDAC inhibitor in ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A024." @default.
• W4296122547 created "2022-09-17" @default.
• W4296122547 creator A5010412450 @default.
• W4296122547 creator A5014794937 @default.
• W4296122547 creator A5017116291 @default.
• W4296122547 creator A5018000478 @default.
• W4296122547 creator A5029397321 @default.
• W4296122547 creator A5036712029 @default.
• W4296122547 creator A5039503529 @default.
• W4296122547 creator A5048290629 @default.
• W4296122547 creator A5050440486 @default.
• W4296122547 creator A5065136823 @default.
• W4296122547 creator A5084482480 @default.
• W4296122547 creator A5087672907 @default.
• W4296122547 date "2022-09-15" @default.
• W4296122547 modified "2023-09-27" @default.
• W4296122547 title "Abstract A024: <i>In vitro</i> efficacy of a novel dual PARP-HDAC inhibitor in ewing sarcoma" @default.
• W4296122547 doi "https://doi.org/10.1158/1557-3265.sarcomas22-a024" @default.
• W4296122547 hasPublicationYear "2022" @default.
• W4296122547 type Work @default.
• W4296122547 citedByCount "0" @default.
• W4296122547 crossrefType "journal-article" @default.
• W4296122547 hasAuthorship W4296122547A5010412450 @default.
• W4296122547 hasAuthorship W4296122547A5014794937 @default.
• W4296122547 hasAuthorship W4296122547A5017116291 @default.
• W4296122547 hasAuthorship W4296122547A5018000478 @default.
• W4296122547 hasAuthorship W4296122547A5029397321 @default.
• W4296122547 hasAuthorship W4296122547A5036712029 @default.
• W4296122547 hasAuthorship W4296122547A5039503529 @default.
• W4296122547 hasAuthorship W4296122547A5048290629 @default.
• W4296122547 hasAuthorship W4296122547A5050440486 @default.
• W4296122547 hasAuthorship W4296122547A5065136823 @default.
• W4296122547 hasAuthorship W4296122547A5084482480 @default.
• W4296122547 hasAuthorship W4296122547A5087672907 @default.
• W4296122547 hasConcept C134935766 @default.
• W4296122547 hasConcept C143425029 @default.
• W4296122547 hasConcept C153911025 @default.
• W4296122547 hasConcept C182979987 @default.
• W4296122547 hasConcept C202751555 @default.
• W4296122547 hasConcept C2778305200 @default.
• W4296122547 hasConcept C2778480876 @default.
• W4296122547 hasConcept C2779138821 @default.
• W4296122547 hasConcept C2779962180 @default.
• W4296122547 hasConcept C502942594 @default.
• W4296122547 hasConcept C53227056 @default.
• W4296122547 hasConcept C552990157 @default.
• W4296122547 hasConcept C55493867 @default.
• W4296122547 hasConcept C64927066 @default.
• W4296122547 hasConcept C82381507 @default.
• W4296122547 hasConcept C86803240 @default.
• W4296122547 hasConcept C98274493 @default.
• W4296122547 hasConceptScore W4296122547C134935766 @default.
• W4296122547 hasConceptScore W4296122547C143425029 @default.
• W4296122547 hasConceptScore W4296122547C153911025 @default.
• W4296122547 hasConceptScore W4296122547C182979987 @default.
• W4296122547 hasConceptScore W4296122547C202751555 @default.
• W4296122547 hasConceptScore W4296122547C2778305200 @default.
• W4296122547 hasConceptScore W4296122547C2778480876 @default.
• W4296122547 hasConceptScore W4296122547C2779138821 @default.
• W4296122547 hasConceptScore W4296122547C2779962180 @default.
• W4296122547 hasConceptScore W4296122547C502942594 @default.
• W4296122547 hasConceptScore W4296122547C53227056 @default.
• W4296122547 hasConceptScore W4296122547C552990157 @default.
• W4296122547 hasConceptScore W4296122547C55493867 @default.
• W4296122547 hasConceptScore W4296122547C64927066 @default.
• W4296122547 hasConceptScore W4296122547C82381507 @default.
• W4296122547 hasConceptScore W4296122547C86803240 @default.
• W4296122547 hasConceptScore W4296122547C98274493 @default.
• W4296122547 hasIssue "18_Supplement" @default.
• W4296122547 hasLocation W42961225471 @default.
• W4296122547 hasOpenAccess W4296122547 @default.
• W4296122547 hasPrimaryLocation W42961225471 @default.
• W4296122547 hasRelatedWork W2145676287 @default.
• W4296122547 hasRelatedWork W2762572114 @default.
• W4296122547 hasRelatedWork W2811095450 @default.
• W4296122547 hasRelatedWork W2811224910 @default.
• W4296122547 hasRelatedWork W2885866858 @default.
• W4296122547 hasRelatedWork W2919317225 @default.
• W4296122547 hasRelatedWork W2979841690 @default.
• W4296122547 hasRelatedWork W3004615009 @default.
• W4296122547 hasRelatedWork W3129062871 @default.
• W4296122547 hasRelatedWork W4361818171 @default.
• W4296122547 hasVolume "28" @default.
• W4296122547 isParatext "false" @default.
• W4296122547 isRetracted "false" @default.
• W4296122547 workType "article" @default.