Comparative analysis of drug-like EP300/CREBBP acetyltransferase inhibitors.
| العنوان: | Comparative analysis of drug-like EP300/CREBBP acetyltransferase inhibitors. |
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| المؤلفون: | Crawford MC; Chemical Biology Laboratory, National Cancer Institute, Frederick, MD, USA., Tripu DR; Chemical Biology Laboratory, National Cancer Institute, Frederick, MD, USA., Barritt SA; Department of Pathology, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA., Jing Y; Chemical Biology Laboratory, National Cancer Institute, Frederick, MD, USA., Gallimore D; Chemical Biology Laboratory, National Cancer Institute, Frederick, MD, USA., Kales SC; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA., Bhanu NV; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA., Xiong Y; Chemical Biology Laboratory, National Cancer Institute, Frederick, MD, USA., Fang Y; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA., Butler KAT; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA., LeClair CA; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA., Coussens NP; Molecular Pharmacology Laboratories, Applied and Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Simeonov A; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA., Garcia BA; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA., Dibble CC; Department of Pathology, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA., Meier JL; Department of Pathology, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2023 May 16. Date of Electronic Publication: 2023 May 16. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | The human acetyltransferase paralogs EP300 and CREBBP are master regulators of lysine acetylation whose activity has been implicated in various cancers. In the half-decade since the first drug-like inhibitors of these proteins were reported, three unique molecular scaffolds have taken precedent: an indane spiro-oxazolidinedione (A-485), a spiro-hydantoin (iP300w), and an aminopyridine (CPI-1612). Despite increasing use of these molecules to study lysine acetylation, the dearth of data regarding their relative biochemical and biological potencies makes their application as chemical probes a challenge. To address this gap, here we present a comparative study of drug-like EP300/CREBBP acetyltransferase inhibitors. First, we determine the biochemical and biological potencies of A-485, iP300w, and CPI-1612, highlighting the increased potency of the latter two compounds at physiological acetyl-CoA concentrations. Cellular evaluation shows that inhibition of histone acetylation and cell growth closely aligns with the biochemical potencies of these molecules, consistent with an on-target mechanism. Finally, we demonstrate the utility of comparative pharmacology by using it to investigate the hypothesis that increased CoA synthesis caused by knockout of PANK4 can competitively antagonize binding of EP300/CREBBP inhibitors and demonstrate proof-of-concept photorelease of a potent inhibitor molecule. Overall, our study demonstrates how knowledge of relative inhibitor potency can guide the study of EP300/CREBBP-dependent mechanisms and suggests new approaches to target delivery, thus broadening the therapeutic window of these preclinical epigenetic drug candidates. |
| التعليقات: | Update in: ACS Chem Biol. 2023 Oct 20;18(10):2249-2258. doi: 10.1021/acschembio.3c00293. (PMID: 37737090) |
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| معلومات مُعتمدة: | ZIA TR000327 United States ImNIH Intramural NIH HHS; R01 HD106051 United States HD NICHD NIH HHS; P01 CA196539 United States CA NCI NIH HHS; HHSN261201500003C United States CA NCI NIH HHS; HHSN261200800001C United States CA NCI NIH HHS; R00 CA194314 United States CA NCI NIH HHS; HHSN261201500003I United States CA NCI NIH HHS; ZIA BC011488 United States ImNIH Intramural NIH HHS; F31 CA254169 United States CA NCI NIH HHS; HHSN261200800001E United States CA NCI NIH HHS |
| تواريخ الأحداث: | Date Created: 20230609 Latest Revision: 20240615 |
| رمز التحديث: | 20240615 |
| مُعرف محوري في PubMed: | PMC10245587 |
| DOI: | 10.1101/2023.05.15.540887 |
| PMID: | 37292747 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.1101/2023.05.15.540887 |
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