Acetyl-CoA biosynthesis drives resistance to histone acetyltransferase inhibition.

التفاصيل البيبلوغرافية
العنوان:	Acetyl-CoA biosynthesis drives resistance to histone acetyltransferase inhibition.
المؤلفون:	Bishop TR; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA., Subramanian C; Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, USA., Bilotta EM; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA., Garnar-Wortzel L; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA., Ramos AR; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA., Zhang Y; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA., Asiaban JN; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA., Ott CJ; Massachusetts General Hospital Cancer Center, Charlestown, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA., Rock CO; Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, USA., Erb MA; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA. michaelerb@scripps.edu.
المصدر:	Nature chemical biology [Nat Chem Biol] 2023 Oct; Vol. 19 (10), pp. 1215-1222. Date of Electronic Publication: 2023 May 01.
نوع المنشور:	Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة:	English
بيانات الدورية:	Publisher: Nature Pub. Group Country of Publication: United States NLM ID: 101231976 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1552-4469 (Electronic) Linking ISSN: 15524450 NLM ISO Abbreviation: Nat Chem Biol Subsets: MEDLINE
أسماء مطبوعة:	Original Publication: New York, NY : Nature Pub. Group, [2005]-
مواضيع طبية MeSH:	Histone Acetyltransferases/metabolism , Neoplasms, Humans ; p300-CBP Transcription Factors/metabolism ; Acetyl Coenzyme A/metabolism ; Protein Binding
مستخلص:	Histone acetyltransferases (HATs) are implicated as both oncogene and nononcogene dependencies in diverse human cancers. Acetyl-CoA-competitive HAT inhibitors have emerged as potential cancer therapeutics and the first clinical trial for this class of drugs is ongoing (NCT04606446). Despite these developments, the potential mechanisms of therapeutic response and evolved drug resistance remain poorly understood. Having discovered that multiple regulators of de novo coenzyme A (CoA) biosynthesis can modulate sensitivity to CBP/p300 HAT inhibition (PANK3, PANK4 and SLC5A6), we determined that elevated acetyl-CoA concentrations can outcompete drug-target engagement to elicit acquired drug resistance. This not only affects structurally diverse CBP/p300 HAT inhibitors, but also agents related to an investigational KAT6A/B HAT inhibitor that is currently in Phase 1 clinical trials. Altogether, this work uncovers CoA metabolism as an unexpected liability of anticancer HAT inhibitors and will therefore buoy future efforts to optimize the efficacy of this new form of targeted therapy. (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
التعليقات:	Comment in: Nat Chem Biol. 2023 Oct;19(10):1174-1175. (PMID: 37127755)
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معلومات مُعتمدة:	DP5 OD026380 United States OD NIH HHS; P30 CA021765 United States CA NCI NIH HHS
سلسلة جزيئية:	ClinicalTrials.gov NCT04606446
المشرفين على المادة:	EC 2.3.1.48 (Histone Acetyltransferases) EC 2.3.1.48 (p300-CBP Transcription Factors) 72-89-9 (Acetyl Coenzyme A) EC 2.3.1.48 (KAT6A protein, human)
تواريخ الأحداث:	Date Created: 20230501 Date Completed: 20230928 Latest Revision: 20240402
رمز التحديث:	20240402
مُعرف محوري في PubMed:	PMC10538425
DOI:	10.1038/s41589-023-01320-7
PMID:	37127754
قاعدة البيانات:	MEDLINE

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تدمد:	1552-4469
DOI:	10.1038/s41589-023-01320-7