在结直肠癌中靶向Beta-catenin:Coltac公司BOND+平台开发的新型分子胶候选药物

beta-Catenin is a central oncogenic driver through its regulation of the Wnt signaling pathway, controlling cell proliferation, metastasis, drug resistance, across multiple cancer types. Its critical role is well-established in colorectal cancer (CRC), hepatocellular carcinoma, endometrial cancer, desmoid tumors, and subsets of ovarian cancer. In over 90% of colorectal cancers, Wnt/beta-catenin pathway mutations elevate beta-catenin levels, promoting tumorigenesis and poor prognosis. Restoring control of aberrant Wnt signaling in beta-catenin-driven cancers hold significant potential to suppress tumor growth and improve clinical outcomes. Targeted protein degradation (TPD) by molecular glues offers a promising therapeutic strategy for modulating oncogenic drivers such as beta-catenin proteins, historically considered challenging for conventional small-molecule inhibition. Discovery of selective glues remains limited by low throughput screening methods, weak detection sensitivity, and the complexity of E3-substrate biology. Coltac Therapeutics developed BOND+ a proprietary bacterial ubiquitin-dependent positive-selection screening system designed to identify molecular glues that enhance E3 ligase-target engagement. This synthetic platform converts functional ubiquitination events into bacterial growth, by leveraging the bacterial environment, which lacks deubiquitinases, proteasomal and lysosomal degradation systems, redundant E3 ligases, and any ubiquitylation-dependent degradation machinery, thus enabling direct, low-signal to noise readouts of functional target engagement. Identified hits are further validated in mammalian cell assays, followed by mechanistic studies and continuous optimization through medicinal chemistry and in silico refinement. Using BOND+ platform we identified selective molecular glue candidates that promote proteasome-dependent degradation of beta-catenin and modulate downstream associated signaling. Lead compounds demonstrated up to 100-fold inhibition potency relative to initial hits, with preferential anti-tumor activity effects in various CRC Wnt-dependent cancer cell models. Early mechanistic studies confirmed target selectivity and E3-ligase dependence. Structure activity relationship (SAR) optimization and in vivo pharmacology studies refined potency and translational potential. Despite beta-catenin central role in CRC there are no approved therapies directly target beta-catenin, highlighting a significant unmet need. Coltac's BOND+ platform enabled rapid discovery and validation supporting therapeutic drugs for beta-catenin. We demonstrated potent antitumor activity highlighting Coltac's molecular glue as a new drug candidate in beta-catenin-driven cancers.