Paralogue-Selective Degradation of the Lysine Acetyltransferase EP300

JACS Au, Год журнала: 2024, Номер 4(8), С. 3094 - 3103

Опубликована: Июль 29, 2024

The transcriptional coactivators EP300 and CREBBP are critical regulators of gene expression that share high sequence identity but exhibit nonredundant functions in basal pathological contexts. Here, we report the development a bifunctional small molecule, MC-1, capable selectively degrading over CREBBP. Using potent aminopyridine-based inhibitor EP300/CREBBP catalytic domain combination with VHL ligand, demonstrate MC-1 preferentially degrades proteasome-dependent manner. Mechanistic studies reveal selective degradation cannot be predicted solely by target engagement or ternary complex formation, suggesting additional factors govern paralogue-specific degradation. inhibits cell proliferation subset cancer lines provides new tool to investigate noncatalytic Our findings expand repertoire EP300/CREBBP-targeting chemical probes offer insights into determinants highly homologous proteins.

Язык: Английский

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Histone methylation and acetylation in cancer: mechanism, progression, and targets

ONCOLOGIE, Год журнала: 2024, Номер unknown

Опубликована: Сен. 18, 2024

Язык: Английский

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Discovery of a Highly Potent PROTAC Degrader of p300/CBP Proteins for the Treatment of Enzalutamide-Resistant Prostate Cancer

Journal of Medicinal Chemistry, Год журнала: 2024, Номер unknown

Опубликована: Сен. 29, 2024

Prostate cancer therapies against androgen receptor (AR) eventually develop lethal resistance; thus, exploring new therapeutic approaches is urgent for prostate treatment. Acetyltransferase p300/CBP are key coactivators AR-mediated transcription and represent promising targets to inhibit AR activity in cancer. We describe the design synthesis evaluation of a class PROTAC degraders. identified an excellent degrader

Язык: Английский

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Paralogue-selective degradation of the lysine acetyltransferase EP300

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Май 5, 2024

Abstract The transcriptional coactivators EP300 and CREBBP are critical regulators of gene expression that share high sequence identity but exhibit non-redundant functions in basal pathological contexts. Here, we report the development a bifunctional small molecule, MC-1, capable selectively degrading over CREBBP. Using potent aminopyridine-based inhibitor EP300/CREBBP catalytic domain combination with VHL ligand, demonstrate MC-1 preferentially degrades proteasome-dependent manner. Mechanistic studies reveal selective degradation cannot be predicted solely by target engagement or ternary complex formation, suggesting additional factors govern paralogue-specific degradation. inhibits cell proliferation subset cancer lines provides new tool to investigate non-catalytic Our findings expand repertoire EP300/CREBBP-targeting chemical probes offer insights into determinants highly homologous proteins.

Язык: Английский

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Selective p300 degradation via peptide PROTAC: a new therapeutic strategy for advanced prostate cancers

EBioMedicine, Год журнала: 2024, Номер 106, С. 105245 - 105245

Опубликована: Июль 8, 2024

Язык: Английский

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