Disabling Oncogenic β-Catenin
Canonical WNT/β-catenin signaling is an oncogenic pathway that connotes poor prognosis in multiple malignances. Although pathway disruption is highly attractive as an anti-cancer strategy, developing agents that selectively modulate proteins that execute the pathway is challenging.
The lab of Dr. Haito Ji (MM) developed a series of alpha-helix-mimicking peptidomimetic disrupters of β-catenin/BCL9, which regulate the expression of downstream target genes. Published in PNAS (2019), these new sulfono-c-AApeptides where shown to mimic the binding mode of the alpha-helical HD2 domain of BCL9. These agents are cell penetrant and have selective β-catenin/BCL9-driven cell-based anti-cancer activity PMID: 31088961.
The Ji lab expanded on these studies in a J Med Chem manuscript (2019) highlighting the development of the first small molecule peptidomimetic mimetics with sub-micromolar affinity to disrupt the β-catenin/BCL9 interaction (PMID: 30856332).
These studies reveal a first-in-class small molecule approach to selectively antagonize β-catenin/BCL9 signaling. Notably, large scale genomic studies demonstrate that WNT/β-catenin signaling contributes to immune evasion across multiple malignances, suggesting that optimized development of these compounds could increase the efficacy of current immune checkpoint inhibitors.