St. Jude Research

EP300 and CBP Binding Compounds (SJ-23-0032)

St. Jude Reference #SJ-23-0032

Description

Researchers from St. Jude Children’s Research Hospital and Dana-Farber Cancer Institute have designed a novel compound to selectively target EP300/CBP in Group 3 medulloblastoma – a subgroup of the most common malignant pediatric brain tumor which is typically challenging to treat. EP300 and CBP play crucial roles in controlling gene transcription, making them attractive targets for therapeutic intervention in cancer. However, traditional inhibitors often target multiple domains, leading to unintended side effects. To address this challenge, researchers conducted a comprehensive analysis using high-potency chemical probes specifically targeting either the HAT or BRD domains of EP300/CBP. 

This analysis led to the design of a small molecule inhibitor, called iCBP4, that is specific for the bromodomain of two proteins, EP300 and CBP.  iCBP4 is based on an existing molecule (CCS1477) with novel modifications. Key advantages include:

  • Increased specificity for EP300 and CBP, with reduced targeting of other proteins, as (compared with CCS1477)
  • Improved pharmacokinetics in mouse serum (half-life, stability)
  • Improved penetration of the blood-brain barrier

Given its improved pharmacokinetics, iCBP4 is more “drug-like” than CCS1477, which is in clinical trials for patients with advanced, hormone-refractory prostate cancer and hematologic malignancies such as AML. iCBP4 is currently being evaluated in preclinical models for effect across a variety of cancer cells and has already shown potent killing of neuroblastoma and medulloblastoma cell lines. The molecule is a possible preclinical candidate for the therapy of EP300/CBP-dependent cancers, which include solid, brain, and hematologic malignancies in many fields; including immunology, cardiology, nephrology, neurology, regenerative medicine/stem cell biology and others.  

A recent publication in Nature Communications details targeting EP300/CBP in Group 3 medulloblastoma – a subgroup of the most common malignant pediatric brain tumor which is typically challenging to treat.

Keywords

HAT, BRO, Bromodomain protein EP300, Bromodomain protein CBP, iCBP4, CCS1477, AML, cancer, neuroblastoma, medulloblastoma, solid tumor, liquid, tumor, brain, hematologic malignancies in many fields; including immunology, cardiology, nephrology, neurology, regenerative medicine/stem cell biology.

Granted patents or published applications

Patent application pending

Related scientific references

Shendy, N.A.M., Bikowitz, M., Sigua, L.H. et al. Group 3 medulloblastoma transcriptional networks collapse under domain specific EP300/CBP inhibition. Nat Commun 15, 3483 (2024). https://doi.org/10.1038/s41467-024-47102-0​​

https://www.nature.com/articles/s41467-024-47102-0

https://www.stjude.org/media-resources/news-releases/2024-medicine-science-news/targeting-specific-protein-regions-offers-new-treatment-approach-medulloblastoma.html

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