Navigating condensate microenvironment to enhance small molecule drug targeting

Many pharmaceutical targets partition into biomolecular condensates, whose microenvironment could significantly influence drug distribution. Nevertheless, it's unclear how small molecule drug design principles should adjust for these partitioned proteins to optimize target engagement. Here, we address this question by systematically investigating how the condensate microenvironment influences drug targeting efficiency. We found condensates formed by intrinsically disordered regions with varying properties highlighted a notable heterogeneity, with nonpolar residue-enriched condensates being more hydrophobic and housing more hydrophobic drugs and endogenous metabolites. Further, the L1000 dataset analysis revealed a strong positive correlation between inhibitor hydrophobicity and targeting efficiency for phase-separated (PS) proteins, represented by ESR1 enriched with nonpolar residues. In cellulo experiments with ESR1 condensates confirmed that both binding affinity and hydrophobicity contribute significantly to enhancing inhibitor potency. These results suggest a new drug design principle for PS proteins by considering condensate microenvironments, potentially leading to more effective drugs that exhibit optimal target engagement.