Solubility based mechanistic profiling of combinatorial drug therapy - PubMed
6 hours ago
- #Proteomics
- #Combinatorial Drug Therapy
- #Acute Myeloid Leukemia
- Introduces CoPISA, a high-throughput proteomics workflow to analyze protein solubility/stability changes induced by drug combinations.
- Applies CoPISA to two AML drug pairs (LY3009120-sapanisertib and ruxolitinib-ulixertinib), uncovering 'conjunctional targeting' as an emergent mechanism.
- Identifies combination-specific protein targets: LS affects SUMOylation, chromatin condensation, and VEGF adhesion; RU disrupts DNA-damage checkpoints, mitochondrial bioenergetics, and RNA-splicing.
- Reveals post-translational modifications (acetylation, methylation, phosphorylation) in key AML proteins like NPM1, and network analysis shows unique targeting of AML-associated proteins.
- Provides a framework for precision-guided combinatorial therapy design in heterogeneous cancers, moving beyond classical synergy models.