BI-3802

Small molecules that induce protein polymerization represent an emerging class of compounds with diverse therapeutic potential. This review provides a comprehensive overview of five such molecules: arsenic trioxide (As₂O₃), BI-3802, NVS-STG2, paclitaxel, and verteporfin. These compounds target different proteins (PML-RARα, BCL6, STING, β-tubulin, and p62, respectively) and exhibit varied mechanisms of action. Some, like As₂O₃ and BI-3802, induce polymerization leading to protein degradation, while others, such as NVS-STG2, activate protein function through polymerization. Paclitaxel, distinct from these, induces the stabilization of tubulin polymers. Verteporfin, on the other hand, uniquely causes covalent cross-linking of its target and other cellular proteins. This review explores the molecular mechanisms, structural insights, and therapeutic implications of these compounds, highlighting their potential in targeted protein degradation, cancer treatment, and modulation of cellular processes, such as autophagy and immune response. The diverse effects of these molecules underscore the complexity of protein polymerization in cellular function and disease, opening new avenues for drug discovery and development.

Biomolecular condensates are membraneless compartments that impart spatial and temporal organization to cells. Condensates can undergo maturation, transitioning from dynamic liquid-like states into solid-like states associated with neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Huntington's disease. Despite their important roles, many aspects of condensate biology remain incompletely understood, requiring tools for acutely manipulating condensate-relevant processes within cells. Here we used the BCL6 BTB domain and its ligands BI-3802 and BI-3812 to create a chemical genetic platform, BTBolig, allowing inducible condensate formation and dissolution. We also developed optogenetic and chemical methods for controlled induction of condensate maturation, where we surprisingly observed recruitment of chaperones into the condensate core and formation of dynamic biphasic condensates. Our work provides insights into the interaction of condensates with proteostasis pathways and introduces a suite of chemical-genetic approaches to probe the role of biomolecular condensates in health and disease.