Graham P. Marsh, Mark S. Cooper, Sean Goggins, Stephen J. Reynolds, Dean F. Wheeler, Joel O. Cresser-Brown, Robert E. Arnold, Emily G. Babcock, Gareth Hughes, Darko Bosnakovski, Michael Kyba, Samuel Ojeda, Drew A. Harrison, Christopher J. Ott and Hannah J. Maple
{"title":"具有增强选择性和降解起始的p300靶向降解物的开发。","authors":"Graham P. Marsh, Mark S. Cooper, Sean Goggins, Stephen J. Reynolds, Dean F. Wheeler, Joel O. Cresser-Brown, Robert E. Arnold, Emily G. Babcock, Gareth Hughes, Darko Bosnakovski, Michael Kyba, Samuel Ojeda, Drew A. Harrison, Christopher J. Ott and Hannah J. Maple","doi":"10.1039/D4MD00969J","DOIUrl":null,"url":null,"abstract":"<p >p300 and CBP are paralogous epigenetic regulators that are considered promising therapeutic targets for cancer treatment. Small molecule p300/CBP inhibitors have so far been unable to differentiate between these closely related proteins, yet selectivity is desirable in order to probe their distinct cellular functions. Additionally, in multiple cancers, loss-of-function <em>CREBBP</em> mutations set up a paralog dependent synthetic lethality with p300, that could be exploited with a selective therapeutic agent. To address this, we developed p300-targeting heterobifunctional degraders that recruit p300 through its HAT domain using the potent spiro-hydantoin-based inhibitor, iP300w. Lead degrader, BT-O2C, demonstrates improved selectivity and a faster onset of action compared to a recently disclosed A 485-based degrader in HAP1 cells and is cytotoxic in CIC::DUX4 sarcoma (CDS) cell lines (IC<small><sub>50</sub></small> = 152–221 nM), significantly reducing expression of CDS target genes (ETV1, ETV4, ETV5). Taken together, our results demonstrate that BT-O2C represents a useful tool degrader for further exploration of p300 degradation as a therapeutic strategy.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 5","pages":" 2049-2060"},"PeriodicalIF":3.5970,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905989/pdf/","citationCount":"0","resultStr":"{\"title\":\"Development of p300-targeting degraders with enhanced selectivity and onset of degradation†\",\"authors\":\"Graham P. Marsh, Mark S. Cooper, Sean Goggins, Stephen J. Reynolds, Dean F. Wheeler, Joel O. Cresser-Brown, Robert E. Arnold, Emily G. Babcock, Gareth Hughes, Darko Bosnakovski, Michael Kyba, Samuel Ojeda, Drew A. Harrison, Christopher J. Ott and Hannah J. Maple\",\"doi\":\"10.1039/D4MD00969J\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >p300 and CBP are paralogous epigenetic regulators that are considered promising therapeutic targets for cancer treatment. Small molecule p300/CBP inhibitors have so far been unable to differentiate between these closely related proteins, yet selectivity is desirable in order to probe their distinct cellular functions. Additionally, in multiple cancers, loss-of-function <em>CREBBP</em> mutations set up a paralog dependent synthetic lethality with p300, that could be exploited with a selective therapeutic agent. To address this, we developed p300-targeting heterobifunctional degraders that recruit p300 through its HAT domain using the potent spiro-hydantoin-based inhibitor, iP300w. Lead degrader, BT-O2C, demonstrates improved selectivity and a faster onset of action compared to a recently disclosed A 485-based degrader in HAP1 cells and is cytotoxic in CIC::DUX4 sarcoma (CDS) cell lines (IC<small><sub>50</sub></small> = 152–221 nM), significantly reducing expression of CDS target genes (ETV1, ETV4, ETV5). Taken together, our results demonstrate that BT-O2C represents a useful tool degrader for further exploration of p300 degradation as a therapeutic strategy.</p>\",\"PeriodicalId\":88,\"journal\":{\"name\":\"MedChemComm\",\"volume\":\" 5\",\"pages\":\" 2049-2060\"},\"PeriodicalIF\":3.5970,\"publicationDate\":\"2025-03-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905989/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"MedChemComm\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://pubs.rsc.org/en/content/articlelanding/2025/md/d4md00969j\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"Pharmacology, Toxicology and Pharmaceutics\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"MedChemComm","FirstCategoryId":"1085","ListUrlMain":"https://pubs.rsc.org/en/content/articlelanding/2025/md/d4md00969j","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"Pharmacology, Toxicology and Pharmaceutics","Score":null,"Total":0}
Development of p300-targeting degraders with enhanced selectivity and onset of degradation†
p300 and CBP are paralogous epigenetic regulators that are considered promising therapeutic targets for cancer treatment. Small molecule p300/CBP inhibitors have so far been unable to differentiate between these closely related proteins, yet selectivity is desirable in order to probe their distinct cellular functions. Additionally, in multiple cancers, loss-of-function CREBBP mutations set up a paralog dependent synthetic lethality with p300, that could be exploited with a selective therapeutic agent. To address this, we developed p300-targeting heterobifunctional degraders that recruit p300 through its HAT domain using the potent spiro-hydantoin-based inhibitor, iP300w. Lead degrader, BT-O2C, demonstrates improved selectivity and a faster onset of action compared to a recently disclosed A 485-based degrader in HAP1 cells and is cytotoxic in CIC::DUX4 sarcoma (CDS) cell lines (IC50 = 152–221 nM), significantly reducing expression of CDS target genes (ETV1, ETV4, ETV5). Taken together, our results demonstrate that BT-O2C represents a useful tool degrader for further exploration of p300 degradation as a therapeutic strategy.
期刊介绍:
Research and review articles in medicinal chemistry and related drug discovery science; the official journal of the European Federation for Medicinal Chemistry.
In 2020, MedChemComm will change its name to RSC Medicinal Chemistry. Issue 12, 2019 will be the last issue as MedChemComm.