Construction and Preclinical evaluation of BCL3-Degrading PROTACs for Enhanced Colorectal Cancer Therapy

Colorectal cancer (CRC), with high incidence and mortality rates, ranks among the most prevalent malignant tumors. Molecular targeted therapies have shown impressive clinical outcomes for CRC therapy. However, the clinical success of targeted treatment of CRC is often limited by resistance. There is a pressing clinical demand for novel targeted therapeutics to enhance the prognosis of CRC patients. B-cell lymphoma 3 (BCL3), an integral constituent of the inhibitory NF-κB (IκB) family, has been reported to be frequently overexpressed in colorectal cancers and involved in the tumor etiology and progression. However, the BCL3 protein lacks “pocket” for covalent inhibitor binding, which prevented the relatively matured covalent inhibitor development. In this study, we have developed a small molecule agent (named PJ1799) targeting and degrading BCL3 via Proteolysis Targeting Chimera (PROTAC) strategy. PJ1799 has been designed to encourage efficient degradation of BCL3 in tumor cells via ubiquitin-proteasome system. As a result, BCL3 demonstrated considerable inhibitory potency for colorectal cancer cells through inactivating multiple key signaling pathways, including the PI3K-AKT and JNK/p38-MAPK pathways. To further enhance the tumor targeting of PJ1799 and address its pharmacological limitations, ligand modification and nanoformulation have been conducted through folic acid conjugate and albumin loading, respectively. The modified PJ1799 drugs possessed promising anti-tumor effects in subcutaneous and intraperitoneal tumor models in vivo without undesired side effects observed. In conclusion, we report here a novel BCL3 targeting PROTAC molecules that may provide potential therapeutic option for colorectal cancer. Besides, PJ1799 serves as a potential probe to explore biological functions of BCL3.