Abstract 3727: Chemical and genetic targeting of epigenetic proteins for cancer therapy
Authors: Qi Jun 
Published: June 2022

Recent evidence suggests that some cancers turn on or off some genes through an entirely a different mechanism, called epigenetics. The robust epigenetic landscape plays a vital role in gene expression via its ability to promote or repress transcription. Reprogramming of these processes can lead to genomic instability, which may propagate a cancerous state. Thus, there are proteins that turn on and off genes can control cell growth and cancer behaviors. Our research focuses to combat this reprogramming utilizing novel small molecules; targeting epigenetic proteins involved in these gene regulatory pathways. Among all the cancer type, the pediatric cancers posted significant challenge for effective therapy development. Despite intense study and cooperative group trials, patients diagnosed with aggressive, high-risk pediatric tumors such as sarcomas, neuroblastoma, high grade gliomas and embryonal brain tumors have poor overall survival outcomes. In addition to the limited efficacy of conventional chemotherapy and radiation in such patients, these modalities are fraught with toxicities, leaving survivors with long-term deficits including infertility, heart failure, endocrine disruption and a risk of secondary malignancies. Thus, one of the most pressing clinical needs in pediatric oncology remains the identification of agents with potent anti-tumor activity that have limited toxicities. Recently, we have utilized both inhibitors and degraders to study the EP300 function in neuroblastoma, an aggressive, hard to treat pediatric cancer. Advances in chemical biology have recently identified a novel group of molecules, called proteolysis-targeted chimaeras (PROTACs) or degrader. These agents may be generated toward any target that has a small molecule binder. To fully assess the therapeutic potential of this novel strategy for pediatric cancers, and potentially for other cancers as well, we set out to target the histone acetyltransferase EP300 that regulates growth and survival in nearly 65% of cancer cell lines, especially in high-risk neuroblastoma. Here, we generated potent and specific reagents, including a lead molecule called JQAD1, that are capable of driving specific degradation of EP300 with limited off-target effects. These compounds induce on-target apoptosis and growth delay in xenografted neuroblastoma tumors, and display excellent pharmacokinetics in vivo without detectable hematologic, hepatic, renal, neurologic or other toxicities. This study showcased our approach to advance cancer research by combining the power of chemistry, chemical biology, structural biology, computational biology and cellular biology. We cover the full spectrum of drug discovery and mechanistic studies for cancer, and also make meaningful and strong collaborations within the cancer research community.

Citation Format: Jun Qi. Chemical and genetic targeting of epigenetic proteins for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3727.