Winship investigators turn cancer mutation into a chemical handle for precision molecular glues

Researchers at Winship Cancer Institute of Emory University and Emory University School of Medicine have reported a significant advance in the development of next-generation anticancer therapeutics: a precision “molecular glue” strategy that converts previously undruggable cancer mutations into actionable drug targets.

Published online in Angewandte Chemie International Edition, the study describes the discovery of a neo-cysteine-targeted covalent molecular glue that selectively restores a protein interaction disrupted by a cancer-associated mutation. The work establishes a framework for designing precision therapies that act specifically in cells carrying defined genetic alterations.

Many genetic alterations in cancer occur in tumor suppressor genes, (the cell’s natural safeguards) and disrupt critical “handshakes” between proteins that regulate growth and survival. Because these mutations disable rather than activate proteins, they have historically been difficult to target with traditional drug approaches.

“What we found is that many of these mutations introduce a specific change, often creating a new cysteine residue that not only drives the damage, but also creates a built-in chemical handle for precision repair using molecular glues,” says Xiulei Mo, PhD, senior author of the paper, assistant professor in the Department of Pharmacology and Chemical Biology at Emory University School of Medicine and a researcher in Winship’s Discovery and Developmental Therapeutics program. “Instead of guessing where a molecular glue binds from our earlier discoveries, the mutation itself tells us exactly where to target. By exploiting these mutation-created ‘neo-cysteines,’ we provide a new strategy to selectively repair those disrupted interactions.”

In this study, the team focused on a mutation in SMAD4, a tumor suppressor protein frequently altered across multiple cancer types. The SMAD4 R361C mutation introduces a neo-cysteine residue at a critical contact point where SMAD4 interacts with its partner protein, SMAD3, weakening this interaction and impairing tumor-suppressive signaling.

Rather than inhibiting overactive oncoproteins, the researchers systematically searched for small molecules that could exploit this mutation-created neo-cysteine to stabilize the disrupted SMAD4–SMAD3 interaction.

Using a high-throughput screening platform developed at the Emory Chemical Biology Discovery Center, investigators screened thousands of cysteine-reactive compounds. This effort led to the discovery of neoCMG101, a first-in-class neo-cysteine molecular glue.

Biochemical, cellular and structural analyses showed that neoCMG101 selectively and covalently modifies the mutation-introduced neo-cysteine on SMAD4. This modification stabilizes the SMAD4–SMAD3 complex and restores downstream signaling activity in cancer cell models carrying the mutation, without affecting the normal protein.

“These results demonstrate that mutation-selective molecular glues can be identified through unbiased screening,” says Haian Fu, PhD, co-author of the study, co-leader of Winship’s Discovery and Developmental Therapeutics program and professor in the Department of Pharmacology and Chemical Biology at Emory University School of Medicine. “This opens the door to targeting a wide range of cancer-associated mutations that were previously considered undruggable.”

The study's first author is Pooja Kumari, PhD, a postdoctoral researcher in Mo's laboratory. Other authors include Yoon Hyeun Oum, PhD, Eric J. Miller, PhD, Min Qui, PhD, Yuhong Du, PhD, Rakesh Singh, PhD, and Hongmei Mou, PhD, representing Winship Cancer Institute, Emory University School of Medicine, Georgia Tech and Massachusetts General Hospital, respectively.

Molecular glues are an emerging class of small-molecule drugs that work by stabilizing or inducing interactions between proteins. While several molecular glues have shown clinical success, most lack mutation specificity.

This study demonstrates that molecular glues can be engineered to act only in the presence of specific cancer mutations. The researchers describe this strategy as targeting the “neo-cysteinome,” the collection of cysteine residues created by disease-causing genetic alterations.

By restoring mutation-disrupted protein interactions, the findings suggest a broadly applicable strategy for precision oncology and other diseases driven by altered protein networks.

The research reflects a multidisciplinary collaboration across Winship Cancer Institute, Emory University School of Medicine and partner institutions, integrating cancer genomics, chemical biology, structural biology and proteomics.

The authors note that further optimization of neo-cysteine molecular glues could enable development of highly selective therapies tailored to individual tumor genotypes. Beyond restoring lost tumor suppressor functions, the approach may also support future proximity-based therapeutic platforms that selectively engage mutant proteins.

“By combining cancer genomics with covalent chemistry and molecular glue pharmacology, we are expanding what is possible in drug discovery,” Mo says. “This work lays the foundation for mutation-directed therapies that are both precise and powerful.”

This work was supported by the National Cancer Institute, including the NCI MERIT Award, the Winship Lung Cancer SPORE and P01 programs and a Winship Invest$ Pilot Grant, with additional support from Winship Cancer Institute, Emory Center for New Medicines and Emory University School of Medicine.