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Updated: Dec 18, 2025
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Discovery of CPI-1612: A Potent, Selective, and Orally Bioavailable EP300/CBP Histone Acetyltransferase Inhibitor
Jonathan E Wilson1, Gaurav Patel2, Chirag Patel2
1Constellation Pharmaceuticals, 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
Abstract:
The histone acetyltransferases, CREB binding protein (CBP) and EP300, are master transcriptional co-regulators that have been implicated in numerous diseases, such as cancer, inflammatory disorders, and neurodegeneration. A novel, highly potent, orally bioavailable EP300/CBP histone acetyltransferase (HAT) inhibitor, CPI-1612 or 17, was developed from the lead compound 3. Replacement of the indole scaffold of 3 with the aminopyridine scaffold of 17 led to improvements in potency, solubility, and bioavailability. These characteristics resulted in a 20-fold lower efficacious dose for 17 relative to lead 3 in a JEKO-1 tumor mouse xenograft study.
Insights
A new drug, CPI-1612 (17), effectively inhibits EP300/CBP histone acetyltransferases. This potent, orally available compound shows improved properties over its predecessor, demonstrating significant therapeutic potential for various diseases.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Histone acetyltransferases CREB binding protein (CBP) and EP300 are key transcriptional co-regulators.
- Dysregulation of CBP/EP300 is linked to cancer, inflammation, and neurodegeneration.
Purpose of the Study:
- To develop a novel, potent, and orally bioavailable inhibitor of EP300/CBP histone acetyltransferases.
- To evaluate the efficacy of the new inhibitor, CPI-1612 (17), compared to a lead compound (3).
Main Methods:
- Medicinal chemistry efforts focused on scaffold modification, replacing the indole of compound 3 with an aminopyridine scaffold to create compound 17 (CPI-1612).
- In vivo efficacy was assessed using a JEKO-1 tumor mouse xenograft model.
Main Results:
- Compound 17 (CPI-1612) demonstrated significantly improved potency, solubility, and oral bioavailability compared to compound 3.
- CPI-1612 required a 20-fold lower efficacious dose than compound 3 in the JEKO-1 xenograft model.
Conclusions:
- The novel aminopyridine-based EP300/CBP HAT inhibitor CPI-1612 (17) represents a promising therapeutic candidate.
- Scaffold modification successfully enhanced drug-like properties and in vivo efficacy, offering potential for treating diseases associated with HAT dysregulation.
