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Discovery of a paralog-selective p300 protein degrader with potent anti-cancer activity in hematological malignancies
Marwa S Asem1, Yan Zhai2, Xiaohong Song2
1Oncology Discovery, AbbVie Inc., North Chicago, IL, USA. Marwa.asem@abbvie.com.
Abstract:
The E1A-associated protein p300 (EP300) is a key regulator of oncogenic transcription factors, making it a promising target for cancer therapy. However, its high sequence similarity to its paralog, CREB-binding protein (CBP), has hindered the development of selective inhibitors, leading to dose-limiting toxicities. Here, we describe the discovery of a highly potent and selective p300 degrader. Unlike dual p300/CBP degraders, this compound forms a more stable ternary complex with p300, driving enhanced proteasomal recruitment and ubiquitination. Notably, our data uncover a previously unrecognized mechanism of paralog selectivity mediated by regioselective ubiquitination of a unique lysine residue on p300. Hematological malignancies, including multiple myeloma, non-Hodgkin lymphoma, and acute myeloid leukemia, exhibit marked sensitivity to selective p300 degradation, resulting in cell lethality and robust antitumor activity in xenograft models. These findings establish selective p300 degradation as a mechanistically distinct and promising therapeutic strategy in hematological malignancies.
Insights
Researchers developed a selective degrader for E1A-associated protein p300 (EP300), a cancer target. This new compound effectively targets EP300 in blood cancers, showing promise for new therapies.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- E1A-associated protein p300 (EP300) is crucial for oncogenic transcription factors and a cancer therapy target.
- Developing selective EP300 inhibitors is challenging due to similarity with CREB-binding protein (CBP), causing dose-limiting toxicities.
Purpose of the Study:
- To discover and characterize a potent and selective EP300 degrader.
- To investigate the mechanism of EP300 selectivity and its therapeutic potential in hematological malignancies.
Main Methods:
- Discovery of a novel EP300 degrader compound.
- Analysis of ternary complex formation, proteasomal recruitment, and ubiquitination.
- Evaluation of selective EP300 degradation in hematological cancer cell lines and xenograft models.
Main Results:
- The novel compound forms a stable ternary complex with EP300, enhancing proteasomal degradation.
- Paralog selectivity is achieved through regioselective ubiquitination at a unique lysine residue on EP300.
- Selective EP300 degradation demonstrated significant cell lethality and antitumor activity in models of multiple myeloma, non-Hodgkin lymphoma, and acute myeloid leukemia.
Conclusions:
- Selective EP300 degradation represents a novel and effective therapeutic strategy for hematological malignancies.
- The discovered EP300 degrader offers a promising new avenue for cancer treatment with improved selectivity.
- Understanding the mechanism of regioselective ubiquitination provides insights for future drug development.
