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 many continue to suffer from significant toxicities. 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 while causing little to no toxicity to normal tissues.
Project Goal: We plan to optimize our EP300 selective degrader for drug development in order to combat toxicity associated with neroblastoma. Additionally, through our open source drug development strategy, we plan to make our molecule available to the cancer research community to further explore the role of EP300 in other pediatric cancers.
Project Update 2022: We have utilized both a chemical and biological approach to confirm that the onco-target EP300 is selectively required in neuroblastoma. Selectively targeting EP300 using our novel degrader JQ-AD1 can effectively inhibit neuroblastoma cancer cell growth in both cell culture condition as well as in an animal model, Our study provides a strong rationale for targeting EP300 selectively as a novel therapeutic strategy. Our medicinal chemistry effort has produced more potent and selective inhibitors. We expect that these studies will uncover deep mechanistic insights into the epigenetics of NB while simultaneously providing a potential novel therapeutic approach to NB and other cancers that depend on EP300 function.
