Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours

Area of Science:

• Epigenetics and Molecular Biology
• Cancer Therapeutics
• Drug Discovery

Background:

• Protein acetylation, regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is a key epigenetic mechanism controlling gene transcription and implicated in diseases.
• While HDAC inhibitors are approved cancer treatments, developing effective HAT inhibitors, particularly for p300 and CREB-binding protein (CBP), has been challenging due to limitations in current drug potency and selectivity.
• p300/CBP are crucial transcriptional co-activators involved in numerous cellular functions and are frequently dysregulated in cancers.

Purpose of the Study:

• To develop and characterize a novel, potent, and selective small molecule inhibitor targeting the catalytic activity of p300 and CBP.
• To elucidate the binding mechanism of the novel inhibitor within the p300 catalytic active site.
• To evaluate the therapeutic potential of the inhibitor in preclinical cancer models, focusing on hematological malignancies and prostate cancer.

Main Methods:

• Design and synthesis of a novel small molecule inhibitor, A-485.
• High-resolution co-crystal structure determination of p300 in complex with A-485.
• Biochemical assays to assess inhibitor potency, selectivity, and mechanism of action (e.g., competition with acetyl-CoA).
• In vitro proliferation assays in various cancer cell lines.
• In vivo efficacy studies using a castration-resistant prostate cancer xenograft model.

Main Results:

• A-485 was identified as a potent and selective inhibitor of p300 and CBP catalytic activity.
• The co-crystal structure revealed A-485 binds to the catalytic active site and competes with acetyl-CoA.
• A-485 demonstrated selective inhibition of proliferation in specific cancer types, including hematological malignancies and androgen receptor-positive prostate cancer.
• In vivo, A-485 inhibited the androgen receptor transcriptional program and reduced tumor growth in a castration-resistant prostate cancer model.

Conclusions:

• Small molecule inhibition of histone acetyltransferase catalytic activity is feasible and can be highly selective.
• A-485 represents a promising therapeutic lead for treating malignancies driven by p300/CBP activity, particularly certain cancers like prostate cancer.
• Targeting HATs offers a viable strategy for developing novel anti-cancer therapies for transcriptional activator-driven diseases.