Abstract LB028: Discovery and characterization of selective heterobifunctional degraders of EP300 in hematopoietic malignancies
Authors: Derheimer Frederick A. , Givarkes Ninvita , Miller Natalie , Grantner Rita , Quinlan Casey , Brun Sonja , Paul Thomas , Ruefli-Brasse Astrid , Steyn Stefan , Bartlett Derek , Hayward Matthew , Brown Matthew , Uccello Daniel , Burke Benjamin J. , Borzilleri Kris , Gilbert Adam , Hemkens Michelle 
Published: April 2024

The paralogous histone acetyltransferases EP300 and CREBBP are two of the master regulators of transcription by controlling both enhancer and promoter activity through histone and non-histone acetylation. EP300 and CREBBP activity is primarily driven by their acetylation of K27 and K18 on histone H3 leading to open and active chromatin state. Targeting the EP300/CREBBP axis of chromatin regulation may be a way to disrupt the signaling pathways downstream of key oncogenic signaling networks like MYC/IRF4 in hematopoietic cancers. Successful development of dual EP300/CREBBP BRDi and HATi has led to promising pre-clinical efficacy, but due to observed tolerability issues may potentially limit their utility in the clinic. We hypothesized, based upon published mouse KO phenotypes, that a selective EP300 compound may improve tolerability. Due to the high sequence homology between EP300 and CREBBP in both the BRD and HAT domains, developing selective inhibitors has proven to be challenging. To combat this, we have utilized heterobifunctional protein degrader technology (ProDegs, also known as PROTACS) to develop EP300 selective ProDegs with greater than 100-fold selectivity over CREBBP. We observe rapid targeted degradation of EP300 with maximal degradation occurring within the first 2-4 hours after treatment. Concomitant with the loss of EP300, we see modulation of the associated H3K27ac and H3K18ac biomarkers as well as alterations in key oncogenic transcription networks. In both in vitro and in vivo assays looking at impact to platelet maturation, we observed that selective loss of EP300 largely abrogated observed thrombocytopenia compared to dual EP300/CREBBP inhibitors. Upon treatment, MM and NHL models show strong downregulation of MYC/IRF4 oncogenic signaling pathways, both of which culminate in a loss of cellular viability and cell death. Additionally, we observe in vivo dose responsive tumor growth inhibition in OPM2 and Pfeiffer xenograft models. Together, the data demonstrate the potential utility of EP300 selective ProDegs for the treatment of hematopoietic malignancies.

Citation Format: Frederick A. Derheimer, Ninvita Givarkes, Natalie Miller, Rita Grantner, Casey Quinlan, Sonja Brun, Thomas Paul, Astrid Ruefli-Brasse, Stefan Steyn, Derek Bartlett, Matthew Hayward, Matthew Brown, Daniel Uccello, Benjamin J. Burke, Kris Borzilleri, Adam Gilbert, Michelle Hemkens. Discovery and characterization of selective heterobifunctional degraders of EP300 in hematopoietic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB028.