Selectively targeting EP300 with small molecules for neuroblastoma (NB) therapy
Neuroblastoma (NB) is the most common pediatric extracranial solid tumor. Although many high-risk neuroblastoma patients respond to conventional radiation and chemotherapy, only half survive and continue to suffer from significant toxicities. With compromised quality of life, they ultimately die of this devastating disease. Novel therapeutics are desperately needed for this disease, especially target specific therapies that will reduce off-target toxicity. Here, we plan to develop an effective strategy for NB by targeting a novel oncoprotein, EP300, which we identified as a dependency in NB. Through our combinatorial chemistry and chemical biology approach, we developed a novel bifunctional molecule JQ-AD1 that can selectively delete EP300 while leaving intact CBP, a close family member of EP300 that is important for normal tissue, but not for NB. Thus, our degrader molecule can stop the growth of neuroblastoma cancer cells causing little to no toxicity to normal tissues.
In this proposal, we will use this powerful tool to further understand why EP300 is a dependency in NB using cancer cells and animal models with the ultimate goal of establishing a pre-clinical rationale. We will optimize our EP300 selective degrader for drug development. Uniquely, we aim to specifically design a drug to address the dire needs of pediatric cancers, contrary to many drugs from industry that are designed for adult cancers. Additionally, through our open source drug development strategy, we will make our molecule available to the cancer research community to further explore the role of EP300 in other pediatric cancers.