2024
Development of a Small Molecule Downmodulator for the Transcription Factor Brachyury
Chase D, Bebenek A, Nie P, Jaime‐Figueroa S, Butrin A, Castro D, Hines J, Linhares B, Crews C. Development of a Small Molecule Downmodulator for the Transcription Factor Brachyury. Angewandte Chemie International Edition 2024, 63: e202316496. PMID: 38348945, DOI: 10.1002/anie.202316496.Peer-Reviewed Original ResearchStructure-based drug design approachX-ray crystallographyDrug design approachMass spectrometryFDA-approved kinase inhibitorsX-raySmall moleculesChordoma cellsCrystallographyTumor cell growthCompoundsChordoma cell linesMoleculesChordoma growthOncogenic transcription factorKinase inhibitorsTranscription factors
2022
OligoTRAFTACs: A generalizable method for transcription factor degradation
Samarasinghe KTG, An E, Genuth MA, Chu L, Holley SA, Crews CM. OligoTRAFTACs: A generalizable method for transcription factor degradation. RSC Chemical Biology 2022, 3: 1144-1153. PMID: 36128504, PMCID: PMC9428672, DOI: 10.1039/d2cb00138a.Peer-Reviewed Original ResearchTranscription factorsOncogenic transcription factorGene expression circuitryTranscription factor degradationDNA binding abilityChordoma cell linesProteasomal degradationProteasomal pathwayZebrafish experimentsC-MycGeneralizable platformKey playersCell linesBrachyurySmall moleculesFactor degradationBinding abilityGeneralizable methodDegradationChimerasPathwayOligonucleotidePocketFirst generation
2021
Targeted protein degradation: A promise for undruggable proteins
Samarasinghe KTG, Crews CM. Targeted protein degradation: A promise for undruggable proteins. Cell Chemical Biology 2021, 28: 934-951. PMID: 34004187, PMCID: PMC8286327, DOI: 10.1016/j.chembiol.2021.04.011.Peer-Reviewed Original ResearchConceptsProteolysis Targeting ChimerasUndruggable proteinsDisease-causing proteinsProtein degradation strategiesProteostasis mechanismsProtein homeostasisTranscription factorsProtein degradationHeterobifunctional moleculesProteinDegradation strategiesDisease initiationBiological effectsProteostasisDegradationPotential therapeutic modalityHomeostasisChimerasCellsAccumulationTargeted degradation of transcription factors by TRAFTACs: TRAnscription Factor TArgeting Chimeras
Samarasinghe KTG, Jaime-Figueroa S, Burgess M, Nalawansha DA, Dai K, Hu Z, Bebenek A, Holley SA, Crews CM. Targeted degradation of transcription factors by TRAFTACs: TRAnscription Factor TArgeting Chimeras. Cell Chemical Biology 2021, 28: 648-661.e5. PMID: 33836141, PMCID: PMC8524358, DOI: 10.1016/j.chembiol.2021.03.011.Peer-Reviewed Original ResearchConceptsTranscription factorsTargeted degradationTranscription factor degradationDNA-binding proteinsMultiple signaling pathwaysGeneralizable strategyDCas9 proteinProtein familyLigandable sitesProteasomal pathwaySignaling pathwaysOverexpression of oncoproteinsAberrant activationChimeric oligonucleotideProteinChimerasFactor degradationNF-κBPathwayHaloTagDegradationBrachyuryOverexpressionOncoproteinOligonucleotide
2016
Novel BET Protein Proteolysis Targeting Chimeras (BETP-PROTACs) Exert Potent Single Agent and Synergistic Activity with Ibrutinib and Venetoclax Against Human Mantle Cell Lymphoma Cells
Sun B, Fiskus W, Zhang L, Raina K, Coleman K, Winkler J, Qian Y, Crew A, Shen A, Saenz D, Mill C, Wang M, Crews C, Bhalla K. Novel BET Protein Proteolysis Targeting Chimeras (BETP-PROTACs) Exert Potent Single Agent and Synergistic Activity with Ibrutinib and Venetoclax Against Human Mantle Cell Lymphoma Cells. Blood 2016, 128: 1058. DOI: 10.1182/blood.v128.22.1058.1058.Peer-Reviewed Original ResearchTarget gene expressionBruton's tyrosine kinaseC-MycARV-825Transcription factorsPrimary MCL cellsTranscriptional activityGene expressionTyrosine kinaseBcl-xLE3 ubiquitin ligase activityMCL cellsUbiquitin ligase activityHuman mantle cell lymphoma cellsB-cell receptor signalingCell receptor signalingBinding of BRD4Regulation of mRNAInk4a/ArfAcetylated chromatinCopy number gainsLigase activityHematopoietic progenitor cellsBET proteinsBETi treatment