Abstract A112: Breaking BRD4: Tailoring E3 ligase recruitment for tumor-selective MYC suppression in pancreatic cancer

Abstract Pancreatic cancer remains one of the most lethal malignancies, with limited therapeutic options and a 5-year survival rate below 12%. MYC, a key driver of pancreatic cancer progression, remains a difficult target due to its lack of defined binding pockets. BRD4, an upstream regulator of MYC, has emerged as a viable target for indirect MYC suppression. However, despite the promise of BRD4 inhibitors, their rapid clearance, low potency, and dose-limiting toxicities have hampered clinical translation. Targeted protein degradation (TPD) using proteolysis-targeting chimeras (PROTACs) offers an alternative approach, leveraging endogenous degradation pathways to achieve sustained target depletion. PROTACs are heterobifunctional molecules that bind a protein of interest and an E3 ubiquitin ligase, promoting proximity-induced ubiquitination and subsequent proteasomal degradation. This strategy can overcome limitations of traditional small molecules, such as resistance mechanisms, lack of sustained inhibition, and difficulty in targeting undruggable proteins. While BRD4-targeting PROTACs show efficacy in cancer types other than pancreatic, their safety profiles remain a concern due to potential on-target effects in normal tissues. The selectivity of PROTACs is governed in part by the recruited E3 ligase, presenting an opportunity to enhance tumor specificity by leveraging E3 ligases differentially expressed in cancer versus normal tissues. Commonly targeted E3 ligases include VHL and CRBN; the ubiquitous, uniform expression profile of VHL limits cancer-cell selectivity, while CRBN expression is decreased in cancerous tissues compared to non-cancerous tissues and cell lines. To promote cancer-cell selectivity, we hypothesize that tuning the E3 ligase-recruiting moiety of a PROTAC to one that is enriched in pancreatic tumors may yield improved tumor selectivity and therapeutic index. To explore this, we have synthesized a panel of novel BRD4-directed PROTACs based on the ARV-771 scaffold, each recruiting a different E3 ligase (CRBN, DCAF16, RNF114). These degraders have been evaluated in pancreatic cancer cell lines and non-cancerous HEK-293 cells, where we observe differential cytotoxic responses and varying potential safety indices, which could be suggestive of E3-dependent effects. Notably, SJM-012, which targets CRBN, had decreased efficacy and safety as compared to the other PROTACs, in agreement with the lower expression of that E3 ligase system in cancers. Work is ongoing examining changes in BRD4 and MYC protein expression over time across pancreatic cancer cell lines. In future studies, we plan to assess target binding and ternary complex formation, as well as evaluate the physicochemical properties. We also intend to explore live-cell degradation and target engagement using NanoBRET and HiBiT-based approaches. Together, these efforts aim to define how E3 ligase selection influences the potency, selectivity, and therapeutic index of degraders in pancreatic cancer, ultimately guiding the rational design of next-generation tumor-selective degraders. Citation Format: Steven J. McKay, Sarah I. Korn, Tracy A. Brooks, Tony D. Davis. Breaking BRD4: Tailoring E3 ligase recruitment for tumor-selective MYC suppression in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A112.