Discovery of a Potent and Selective Covalent p300/CBP Inhibitor

Area of Science:

• Biochemistry and Molecular Biology
• Chemical Biology
• Drug Discovery

Background:

• Aberrant histone acetyltransferase (HAT) activity of p300 and CREB binding protein (CBP) is implicated in various diseases, including cancers.
• Existing therapeutic strategies primarily focus on noncovalent inhibitors of p300/CBP.
• Structural insights reveal a reactive cysteine residue (C1450) near the active site of p300/CBP, suggesting covalent inhibition as a viable approach.

Purpose of the Study:

• To develop and characterize a novel covalent inhibitor targeting p300 and CBP.
• To investigate the selectivity and mechanism of action of the developed covalent inhibitor.
• To provide a new chemical tool for exploring p300/CBP biological functions.

Main Methods:

• Design and synthesis of an acrylamide-based covalent inhibitor (compound 2).
• Mass spectrometry to confirm selective targeting of C1450.
• Enzyme kinetics and cellular washout studies to validate covalent binding.

Main Results:

• Compound 2 was successfully developed as an acrylamide-based inhibitor of p300/CBP.
• Mass spectrometry confirmed that compound 2 selectively forms a covalent adduct with C1450.
• Kinetics and cellular studies validated the covalent nature of the inhibition.

Conclusions:

• The development of compound 2 provides a selective covalent inhibitor for p300/CBP.
• This novel inhibitor offers a valuable chemical probe for studying p300/CBP in biological systems.
• Covalent inhibition targeting C1450 represents a promising strategy for modulating p300/CBP activity.