Molecular glues designed to selectively bind mutated neo-cysteine residues and restore disease-disrupted protein–protein interactions (PPIs), offering a precision therapeutic approach for conditions such as cancer where loss or weakening of critical protein interactions drives tumor growth and progression.
The global precision oncology market is experiencing strong growth, driven by advances in genomics, biomarker discovery, and targeted therapies. This sector is projected to expand steadily as cancer incidence remains high worldwide and healthcare systems increasingly adopt personalized treatment strategies. Emerging precision oncology strategies increasingly focus on exploiting recurrent genetic mutations in tumor suppressors and oncogenes, such as TP53 and SMAD4. Importantly, large-scale cancer genomic studies have revealed a substantial number of disease-associated mutations that introduce neo-cysteine residues and weaken critical protein–protein interactions (hypoPPIs), creating a broad and previously underexploited therapeutic opportunity. These mutations occur across almost all cancer types, such as pancreatic, colorectal, and lung cancers, representing a significant patient population. Traditional drug discovery struggles to target protein interactions weakened by disease-related mutations, and existing cysteine-reactive covalent drugs often lack mutation-specific selectivity, increasing the risk of off-target toxicity. The presence of mutation-encoded neo-cysteines at disrupted PPI interfaces offers a unique chemical handle for highly selective covalent engagement. Therefore, there is a significant unmet need for precision therapeutic approaches that can selectively restore these specific, disrupted protein interactions in genetically defined patient populations.
Emory researchers have identified a precision therapeutic approach using small molecule covalent modifiers, termed neo-cysteine targeted covalent molecular glues (neoCMGs), to selectively restore disrupted protein-protein interactions (PPIs) in cancer. The core problem addressed by this technology is the difficulty in therapeutically targeting PPIs disrupted by cancer-specific genetic mutations. These disruptions, often creating “hypomorphic PPIs” (hypoPPIs), are crucial to cancer progression but are challenging drug targets. These mutations can also introduce “neo-cysteine” residues, which are present only in the mutated protein and often located at these disrupted PPI interfaces. The technology identifies and leverages the unique chemical reactivity of mutation-derived neo-cysteine residues. Additionally, it establishes a generalizable framework and systematic approach for discovering
Proof-of-principle has been demonstrated, and a lead candidate has been identified.
Publication
Xiulei Mo, Yuhong Du, Haian Fu. “Evaluation of molecular glue–induced neomorphic protein-protein interaction with a cell lysate–based time-resolved fluorescence resonance energy transfer assay”. ASPET Discovery, Volume 1, 2025, 100003. https://doi.org/10.1016/j.aspetd.2025.100003