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Comparative Analysis of Drug-like EP300/CREBBP Acetyltransferase Inhibitors
McKenna C Crawford1, Deepika R Tripu1, Samuel A Barritt2
1Chemical Biology Laboratory, National Cancer Institute, Frederick, Maryland 21702, United States.
ACS Chemical Biology
|September 22, 2023
Summary
Comparing EP300/CREBBP inhibitors reveals potency differences crucial for cancer research. Understanding these acetyltransferase inhibitors guides epigenetic drug development and delivery strategies.
Area of Science:
- Biochemistry
- Molecular Biology
- Epigenetics
Background:
- EP300 and CREBBP are key regulators of lysine acetylation involved in cancer.
- Existing EP300/CREBBP inhibitors (A-485, iP300w, CPI-1612) lack comparative potency data, hindering their use as chemical probes.
Purpose of the Study:
- To comparatively assess the biochemical and biological potencies of three drug-like EP300/CREBBP inhibitors.
- To evaluate the correlation between inhibitor potency, histone acetylation, and cell growth.
- To explore competitive antagonism of inhibitors by CoA synthesis and investigate targeted delivery.
Main Methods:
- Biochemical and cellular assays to determine inhibitor potencies.
- Assessment of histone acetylation and cell growth inhibition.
- Pharmacological studies involving PANK4 knockout and photorelease technology.
Main Results:
- iP300w and CPI-1612 exhibit greater potency than A-485 at physiological acetyl-CoA levels.
- Inhibition of histone acetylation and cell growth correlates with biochemical potencies, indicating on-target effects.
- Demonstrated competitive antagonism by increased CoA synthesis and proof-of-concept for targeted inhibitor delivery.
Conclusions:
- Relative inhibitor potency is critical for studying EP300/CREBBP-dependent mechanisms.
- Comparative pharmacology aids in understanding drug interactions and optimizing epigenetic drug candidates.
- New strategies for targeted delivery can potentially broaden the therapeutic window for EP300/CREBBP inhibitors.
