{"id":"https://openalex.org/W4361846271","doi":"https://doi.org/10.1158/0008-5472.c.6510722.v1","title":"Data from MDM2-Recruiting PROTAC Offers Superior, Synergistic Antiproliferative Activity via Simultaneous Degradation of BRD4 and Stabilization of p53","display_name":"Data from MDM2-Recruiting PROTAC Offers Superior, Synergistic Antiproliferative Activity via Simultaneous Degradation of BRD4 and Stabilization of p53","publication_year":2023,"publication_date":"2023-03-31","ids":{"openalex":"https://openalex.org/W4361846271","doi":"https://doi.org/10.1158/0008-5472.c.6510722.v1"},"language":"en","primary_location":{"id":"doi:10.1158/0008-5472.c.6510722.v1","doi":"https://doi.org/10.1158/0008-5472.c.6510722.v1","is_oa":true,"landing_page_url":"http://dx.doi.org/10.1158/0008-5472.c.6510722.v1","pdf_url":null,"source":null,"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"acceptedVersion","is_accepted":true,"is_published":false,"raw_source_name":"American Association for Cancer Research","raw_type":"posted-content"},"volume":null,"type":"other","indexed_in":["crossref"],"open_access":{"is_oa":true,"oa_status":"gold","oa_url":"http://dx.doi.org/10.1158/0008-5472.c.6510722.v1","any_repository_has_fulltext":null},"authorships":[{"author_position":"first","author":{"id":"https://openalex.org/A5111710470","display_name":"John Hines","orcid":null,"observed_orcids":[]},"institutions":[],"countries":[],"is_corresponding":false,"raw_author_name":"John Hines","raw_affiliation_strings":[],"raw_orcid":null,"affiliations":[]},{"author_position":"middle","author":{"id":"https://openalex.org/A5052979030","display_name":"Schan Lartigue","orcid":null,"observed_orcids":[]},"institutions":[],"countries":[],"is_corresponding":false,"raw_author_name":"Schan Lartigue","raw_affiliation_strings":[],"raw_orcid":null,"affiliations":[]},{"author_position":"middle","author":{"id":"https://openalex.org/A5112271127","display_name":"Hanqing Dong","orcid":null,"observed_orcids":[]},"institutions":[],"countries":[],"is_corresponding":false,"raw_author_name":"Hanqing Dong","raw_affiliation_strings":[],"raw_orcid":null,"affiliations":[]},{"author_position":"middle","author":{"id":"https://openalex.org/A5021167157","display_name":"Yimin Qian","orcid":"https://orcid.org/0000-0003-2377-7931","observed_orcids":["https://orcid.org/0000-0003-2377-7931"]},"institutions":[],"countries":[],"is_corresponding":false,"raw_author_name":"Yimin Qian","raw_affiliation_strings":[],"raw_orcid":null,"affiliations":[]},{"author_position":"last","author":{"id":"https://openalex.org/A5016866989","display_name":"Craig M. Crews","orcid":"https://orcid.org/0000-0002-8456-2005","observed_orcids":["https://orcid.org/0000-0002-8456-2005"]},"institutions":[],"countries":[],"is_corresponding":false,"raw_author_name":"Craig M. Crews","raw_affiliation_strings":[],"raw_orcid":"https://orcid.org/0000-0002-8456-2005","affiliations":[]}],"institutions":[],"countries_distinct_count":0,"institutions_distinct_count":0,"corresponding_author_ids":[],"corresponding_institution_ids":[],"apc_list":null,"apc_paid":null,"fwci":null,"has_fulltext":false,"cited_by_count":0,"citation_normalized_percentile":null,"cited_by_percentile_year":null,"biblio":{"volume":null,"issue":null,"first_page":null,"last_page":null},"is_retracted":false,"is_paratext":false,"is_xpac":false,"primary_topic":{"id":"https://openalex.org/T12534","display_name":"Protein Degradation and Inhibitors","score":1.0,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},"topics":[{"id":"https://openalex.org/T12534","display_name":"Protein Degradation and Inhibitors","score":1.0,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T10583","display_name":"Cancer-related Molecular Pathways","score":0.0,"subfield":{"id":"https://openalex.org/subfields/2730","display_name":"Oncology"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},{"id":"https://openalex.org/T11041","display_name":"Ubiquitin and proteasome pathways","score":0.0,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}}],"keywords":[{"id":"https://openalex.org/keywords/protacs","display_name":"PROTACs","score":0.843999981880188},{"id":"https://openalex.org/keywords/mdm2","display_name":"MDM2","score":0.9129999876022339},{"id":"https://openalex.org/keywords/brd4-degradation","display_name":"BRD4 degradation","score":0.8209999799728394},{"id":"https://openalex.org/keywords/p53-stabilization","display_name":"p53 stabilization","score":0.9769999980926514},{"id":"https://openalex.org/keywords/nutlin","display_name":"nutlin","score":0.8510000109672546},{"id":"https://openalex.org/keywords/e3-ubiquitin-ligase","display_name":"E3 ubiquitin ligase","score":0.7369999885559082},{"id":"https://openalex.org/keywords/vhl","display_name":"VHL","score":0.5329999923706055},{"id":"https://openalex.org/keywords/antiproliferative-activity","display_name":"antiproliferative activity","score":0.8339999914169312},{"id":"https://openalex.org/keywords/drug-synergy","display_name":"drug synergy","score":0.546999990940094},{"id":"https://openalex.org/keywords/heterobifunctional-molecules","display_name":"heterobifunctional molecules","score":0.7350000143051147},{"id":"https://openalex.org/keywords/cancer-cell-lines","display_name":"cancer cell lines","score":0.5199999809265137},{"id":"https://openalex.org/keywords/targeted-protein-degradation","display_name":"targeted protein degradation","score":0.7559999823570251}],"concepts":[{"id":"https://openalex.org/C134459356","wikidata":"https://www.wikidata.org/wiki/Q4274835","display_name":"Ubiquitin ligase","level":4,"score":0.8114492297172546},{"id":"https://openalex.org/C2776192174","wikidata":"https://www.wikidata.org/wiki/Q18028978","display_name":"Mdm2","level":3,"score":0.6560654640197754},{"id":"https://openalex.org/C25602115","wikidata":"https://www.wikidata.org/wiki/Q407111","display_name":"Ubiquitin","level":3,"score":0.6300196051597595},{"id":"https://openalex.org/C185592680","wikidata":"https://www.wikidata.org/wiki/Q2329","display_name":"Chemistry","level":0,"score":0.5394154191017151},{"id":"https://openalex.org/C2779634854","wikidata":"https://www.wikidata.org/wiki/Q18037206","display_name":"BRD4","level":5,"score":0.49601754546165466},{"id":"https://openalex.org/C173396325","wikidata":"https://www.wikidata.org/wiki/Q1501275","display_name":"Gene knockdown","level":3,"score":0.483864426612854},{"id":"https://openalex.org/C502942594","wikidata":"https://www.wikidata.org/wiki/Q3421914","display_name":"Cancer research","level":1,"score":0.4689115285873413},{"id":"https://openalex.org/C95444343","wikidata":"https://www.wikidata.org/wiki/Q7141","display_name":"Cell biology","level":1,"score":0.46795427799224854},{"id":"https://openalex.org/C2992195973","wikidata":"https://www.wikidata.org/wiki/Q33123","display_name":"Protein degradation","level":2,"score":0.4389348030090332},{"id":"https://openalex.org/C86803240","wikidata":"https://www.wikidata.org/wiki/Q420","display_name":"Biology","level":0,"score":0.29956305027008057},{"id":"https://openalex.org/C55493867","wikidata":"https://www.wikidata.org/wiki/Q7094","display_name":"Biochemistry","level":1,"score":0.2931153178215027},{"id":"https://openalex.org/C74401373","wikidata":"https://www.wikidata.org/wiki/Q1829843","display_name":"Bromodomain","level":4,"score":0.1693674921989441},{"id":"https://openalex.org/C190283241","wikidata":"https://www.wikidata.org/wiki/Q14599311","display_name":"Apoptosis","level":2,"score":0.1291806399822235},{"id":"https://openalex.org/C552990157","wikidata":"https://www.wikidata.org/wiki/Q7430","display_name":"DNA","level":2,"score":0.112070232629776},{"id":"https://openalex.org/C104317684","wikidata":"https://www.wikidata.org/wiki/Q7187","display_name":"Gene","level":2,"score":0.07054510712623596},{"id":"https://openalex.org/C64927066","wikidata":"https://www.wikidata.org/wiki/Q36293","display_name":"Histone","level":3,"score":0.06624835729598999}],"mesh":[],"locations_count":1,"locations":[{"id":"doi:10.1158/0008-5472.c.6510722.v1","doi":"https://doi.org/10.1158/0008-5472.c.6510722.v1","is_oa":true,"landing_page_url":"http://dx.doi.org/10.1158/0008-5472.c.6510722.v1","pdf_url":null,"source":null,"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"acceptedVersion","is_accepted":true,"is_published":false,"raw_source_name":"American Association for Cancer Research","raw_type":"posted-content"}],"best_oa_location":{"id":"doi:10.1158/0008-5472.c.6510722.v1","doi":"https://doi.org/10.1158/0008-5472.c.6510722.v1","is_oa":true,"landing_page_url":"http://dx.doi.org/10.1158/0008-5472.c.6510722.v1","pdf_url":null,"source":null,"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"acceptedVersion","is_accepted":true,"is_published":false,"raw_source_name":"American Association for Cancer Research","raw_type":"posted-content"},"sustainable_development_goals":[{"display_name":"Good health and well-being","id":"https://metadata.un.org/sdg/3","score":0.9476000070571899}],"study_designs":[],"awards":[],"funders":[],"has_content":{"pdf":false,"grobid_xml":false},"content_urls":null,"referenced_works_count":0,"referenced_works":[],"related_works":["https://openalex.org/W2898621430","https://openalex.org/W4410027845","https://openalex.org/W7163046965","https://openalex.org/W4281862348","https://openalex.org/W4293490516","https://openalex.org/W7120139903","https://openalex.org/W4377020199","https://openalex.org/W4411012253","https://openalex.org/W4368358799","https://openalex.org/W4399116562"],"abstract_inverted_index":{"Abstract":[0],"Although":[1,39],"the":[2,16,30,40,47,70,76,105,116,149,157,174,183,198],"number":[3,17],"of":[4,18,50,78,108,125,152,185,215],"proteins":[5],"effectively":[6],"targeted":[7],"for":[8,32],"posttranslational":[9],"degradation":[10],"by":[11,46,99,181,192],"PROTAC":[12,61,81,118,138,154,202],"has":[13,26],"grown":[14],"steadily,":[15],"E3":[19,41,158,186],"ligases":[20,187],"successfully":[21],"exploited":[22],"to":[23,29,82,94,110,144,165],"accomplish":[24],"this":[25,216],"been":[27,37],"limited":[28],"few":[31,55],"which":[33,156],"small-molecule":[34,51],"ligands":[35],"have":[36],"discovered.":[38],"ligase":[42,159],"MDM2":[43],"is":[44,148],"bound":[45],"nutlin":[48],"class":[49],"ligands,":[52],"there":[53],"are":[54],"nutlin-based":[56,60,117],"PROTAC.":[57,193],"Because":[58],"a":[59,80,135,153,167],"should":[62],"both":[63,213],"knockdown":[64],"its":[65,96],"target":[66,97],"protein":[67,98],"and":[68,142,161,207],"upregulate":[69],"tumor":[71],"suppressor":[72],"p53,":[73,112],"we":[74,113],"examined":[75],"ability":[77,107],"such":[79],"decrease":[83],"cancer":[84,127],"cell":[85,128],"viability.":[86],"A":[87],"nutlin-based,":[88],"BRD4-degrading":[89],"PROTAC,":[90],"A1874,":[91],"was":[92,119,134],"able":[93],"degrade":[95,145],"98%":[100],"with":[101,130,139,212],"nanomolar":[102],"potency.":[103],"Given":[104],"complementary":[106],"A1874":[109],"stabilize":[111],"discovered":[114],"that":[115,177,188,203],"more":[120],"effective":[121],"in":[122,155],"inhibiting":[123],"proliferation":[124],"many":[126],"lines":[129],"wild-type":[131],"p53":[132],"than":[133],"corresponding":[136],"VHL-utilizing":[137],"similar":[140],"potency":[141],"efficacy":[143],"BRD4.":[146],"This":[147],"first":[150,199],"report":[151],"ligand":[160],"targeting":[162],"warhead":[163],"combine":[164],"exert":[166],"synergistic":[168,208],"antiproliferative":[169],"effect.":[170],"Our":[171],"study":[172],"highlights":[173],"untapped":[175],"potential":[176],"may":[178],"be":[179,190],"unlocked":[180],"expanding":[182],"repertoire":[184],"can":[189],"recruited":[191],"Significance:":[194],"These":[195],"findings":[196],"present":[197],"BRD4-targeting":[200],"MDM2-based":[201],"possesses":[204],"potent,":[205],"distinct,":[206],"biological":[209],"activities":[210],"associated":[211],"ends":[214],"heterobifunctional":[217],"molecule.":[218]},"counts_by_year":[],"updated_date":"2026-08-21T09:56:20.448147","created_date":"2023-04-05T00:00:00"}
