FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W1489059557> ?p ?o ?g. }

• W1489059557 abstract "Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CAThe protein-protein interaction (PPI) between menin and Mixed Lineage Leukemia (MLL) plays a critical role in acute leukemias with translocations of MLL gene, and inhibition of this interaction with small molecules represents a new potential therapeutic strategy for the MLL leukemia patients. We identified novel small molecule inhibitors of the menin-MLL interaction with distinct molecular scaffolds by performing a High Throughput Screening (HTS) of over 300,000 compounds. Extensive medicinal chemistry efforts performed for two lead classes to improve inhibitory activity of these compounds resulted in menin-MLL inhibitors with low nanomolar binding affinities. The menin-inhibitor co-crystal structures revealed that these compounds directly bind to menin and closely mimic the key interactions of MLL with menin, resulting in their high binding affinity. Interestingly, the hydroxymethylpiperidine class of the menin-MLL inhibitors extends beyond the MLL binding region on menin, providing additional opportunity for their optimization. We combined extensive crystallography studies with structure-based design to perform rational optimization and scaffold modification to rapidly improve activity and modulate physicochemical properties of the menin-MLL inhibitors. Treatment of MLL leukemia cells with the most potent menin-MLL inhibitors we developed resulted in very effective and selective inhibition of cell proliferation, induced apoptosis and differentiation of these cells. These effects were associated with downregulation of Hoxa9 and Meis1 expression, the downstream targets of MLL fusion proteins required for their leukemogenicity, demonstrating a very specific mechanism of action for these newly developed menin-MLL inhibitors. In vivo studies are currently undergoing to assess the effect of these compounds on leukemia progression in animal models of MLL leukemia. Our studies provide a novel and very attractive scaffolds for further development as a new potential therapeutic approach for the MLL leukemia patients.Citation Format: Jolanta E. Grembecka, Shihan He, Timothy J. Senter, Dmitry Borkin, Jonathan Pollock, Changho Han, Sunil Kumar Upadhyay, Trupta Purohit, Hongzhi Miao, Rocco D. Gogliotti D. Gogliotti, Craig W. Lindsley, Tomasz Cierpicki, Shaun R. Stauffer. High-affinity small molecule inhibitors of the menin-MLL interaction reverse oncogenic transformation mediated by MLL fusion proteins in leukemia. [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 2534. doi:10.1158/1538-7445.AM2014-2534" @default.
• W1489059557 created "2016-06-24" @default.
• W1489059557 creator A5011882158 @default.
• W1489059557 creator A5013432515 @default.
• W1489059557 creator A5024134821 @default.
• W1489059557 creator A5026691889 @default.
• W1489059557 creator A5034916482 @default.
• W1489059557 creator A5060483072 @default.
• W1489059557 creator A5072277704 @default.
• W1489059557 creator A5077095928 @default.
• W1489059557 creator A5079389438 @default.
• W1489059557 creator A5080373326 @default.
• W1489059557 creator A5080568394 @default.
• W1489059557 creator A5084249783 @default.
• W1489059557 creator A5087287506 @default.
• W1489059557 date "2014-09-30" @default.
• W1489059557 modified "2023-09-26" @default.
• W1489059557 title "Abstract 2534: High-affinity small molecule inhibitors of the menin-MLL interaction reverse oncogenic transformation mediated by MLL fusion proteins in leukemia" @default.
• W1489059557 doi "https://doi.org/10.1158/1538-7445.am2014-2534" @default.
• W1489059557 hasPublicationYear "2014" @default.
• W1489059557 type Work @default.
• W1489059557 sameAs 1489059557 @default.
• W1489059557 citedByCount "0" @default.
• W1489059557 crossrefType "proceedings-article" @default.
• W1489059557 hasAuthorship W1489059557A5011882158 @default.
• W1489059557 hasAuthorship W1489059557A5013432515 @default.
• W1489059557 hasAuthorship W1489059557A5024134821 @default.
• W1489059557 hasAuthorship W1489059557A5026691889 @default.
• W1489059557 hasAuthorship W1489059557A5034916482 @default.
• W1489059557 hasAuthorship W1489059557A5060483072 @default.
• W1489059557 hasAuthorship W1489059557A5072277704 @default.
• W1489059557 hasAuthorship W1489059557A5077095928 @default.
• W1489059557 hasAuthorship W1489059557A5079389438 @default.
• W1489059557 hasAuthorship W1489059557A5080373326 @default.
• W1489059557 hasAuthorship W1489059557A5080568394 @default.
• W1489059557 hasAuthorship W1489059557A5084249783 @default.
• W1489059557 hasAuthorship W1489059557A5087287506 @default.
• W1489059557 hasConcept C104317684 @default.
• W1489059557 hasConcept C111829193 @default.
• W1489059557 hasConcept C11804247 @default.
• W1489059557 hasConcept C121608353 @default.
• W1489059557 hasConcept C123894998 @default.
• W1489059557 hasConcept C127561419 @default.
• W1489059557 hasConcept C161624437 @default.
• W1489059557 hasConcept C174510640 @default.
• W1489059557 hasConcept C185592680 @default.
• W1489059557 hasConcept C2778461978 @default.
• W1489059557 hasConcept C40767141 @default.
• W1489059557 hasConcept C502942594 @default.
• W1489059557 hasConcept C54355233 @default.
• W1489059557 hasConcept C55493867 @default.
• W1489059557 hasConcept C70721500 @default.
• W1489059557 hasConcept C86803240 @default.
• W1489059557 hasConcept C95444343 @default.
• W1489059557 hasConceptScore W1489059557C104317684 @default.
• W1489059557 hasConceptScore W1489059557C111829193 @default.
• W1489059557 hasConceptScore W1489059557C11804247 @default.
• W1489059557 hasConceptScore W1489059557C121608353 @default.
• W1489059557 hasConceptScore W1489059557C123894998 @default.
• W1489059557 hasConceptScore W1489059557C127561419 @default.
• W1489059557 hasConceptScore W1489059557C161624437 @default.
• W1489059557 hasConceptScore W1489059557C174510640 @default.
• W1489059557 hasConceptScore W1489059557C185592680 @default.
• W1489059557 hasConceptScore W1489059557C2778461978 @default.
• W1489059557 hasConceptScore W1489059557C40767141 @default.
• W1489059557 hasConceptScore W1489059557C502942594 @default.
• W1489059557 hasConceptScore W1489059557C54355233 @default.
• W1489059557 hasConceptScore W1489059557C55493867 @default.
• W1489059557 hasConceptScore W1489059557C70721500 @default.
• W1489059557 hasConceptScore W1489059557C86803240 @default.
• W1489059557 hasConceptScore W1489059557C95444343 @default.
• W1489059557 hasLocation W14890595571 @default.
• W1489059557 hasOpenAccess W1489059557 @default.
• W1489059557 hasPrimaryLocation W14890595571 @default.
• W1489059557 hasRelatedWork W1560166507 @default.
• W1489059557 hasRelatedWork W1983985145 @default.
• W1489059557 hasRelatedWork W1994598503 @default.
• W1489059557 hasRelatedWork W2008730812 @default.
• W1489059557 hasRelatedWork W2025570007 @default.
• W1489059557 hasRelatedWork W2037856618 @default.
• W1489059557 hasRelatedWork W2056781744 @default.
• W1489059557 hasRelatedWork W2069591815 @default.
• W1489059557 hasRelatedWork W2078404121 @default.
• W1489059557 hasRelatedWork W2170187767 @default.
• W1489059557 hasRelatedWork W2508029612 @default.
• W1489059557 hasRelatedWork W2551730662 @default.
• W1489059557 hasRelatedWork W2594167446 @default.
• W1489059557 hasRelatedWork W2777307770 @default.
• W1489059557 hasRelatedWork W2799607270 @default.
• W1489059557 hasRelatedWork W2799870037 @default.
• W1489059557 hasRelatedWork W2979032940 @default.
• W1489059557 hasRelatedWork W3021909182 @default.
• W1489059557 hasRelatedWork W3027306734 @default.
• W1489059557 hasRelatedWork W2741971406 @default.
• W1489059557 isParatext "false" @default.
• W1489059557 isRetracted "false" @default.
• W1489059557 magId "1489059557" @default.
• W1489059557 workType "article" @default.