Unlocking New Frontiers in Drug Discovery: The Promise of Molecular Glues

Molecular glues represent a revolutionary class of small molecules in modern therapeutics. Unlike traditional drugs that bind to specific pockets on target proteins, these innovative compounds act as matchmakers, inducing or stabilizing interactions between proteins that would otherwise not associate. This mechanism allows them to modulate protein-protein interactions (PPIs), a vast landscape previously deemed undruggable due to the flat, featureless surfaces involved.

In Singapore's vibrant biotech ecosystem, researchers at the Agency for Science, Technology and Research (A*STAR) are at the forefront of this paradigm shift. Their latest publication in the prestigious Journal of Medicinal Chemistry outlines a transition from serendipitous discoveries to rational design strategies, promising to expand the druggable proteome significantly.

From Serendipity to Systematic Science: The Evolution of Molecular Glue Research

The journey of molecular glues began decades ago with compounds like cyclosporin A and FK506, identified inadvertently during immunosuppression studies. These molecules formed ternary complexes—protein-small molecule-protein—stabilizing interactions between cyclophilin and calcineurin, effectively blocking T-cell activation. Such early finds highlighted the potential but lacked predictability.

Over time, advances in high-throughput screening (HTS), DNA-encoded libraries (DELs), fragment-based approaches, and computational modeling have enabled targeted hunts. The A*STAR team's review details two primary mechanisms: the 'binder-first' model, where the glue alters a protein's surface to recruit a partner, and the stabilization of weak native PPIs via a composite pocket. Examples include lenalidomide recruiting neosubstrates to CRBN E3 ligase for degradation, and emerging covalent glues like zoldonrasib for KRAS G12D.

This evolution is crucial for Singapore, where A*STAR's Experimental Drug Development Centre (EDDC) leverages structural biology and computational chemistry to accelerate such innovations.

A*STAR's Key Contributors: Expertise Driving Innovation

Co-author Congbao Kang, who leads the structural biology team at EDDC, brings deep expertise in NMR spectroscopy for membrane proteins and drug-target interactions. His work has supported fragment screening and mechanism elucidation for diverse modalities. Weijun Xu, heading computational chemistry at EDDC, complements this with skills in molecular modeling and AI-aided design, bridging structure and simulation for rational glue development.

David E. Heppner from SUNY Buffalo rounds out the team, providing insights from US academia. Their collaboration underscores Singapore's role in global networks, with EDDC partnering industry like Daiichi Sankyo and RDP Pharma on degraders.

Mechanisms Unveiled: How Molecular Glues Work

Molecular glues operate via two models. In binder-first, the glue binds one protein, creating a neosurface for the second. Native weak PPIs form pockets stabilized by the glue. Structural snapshots reveal diversity: filaments (BI-3802-BCL6), GPCR modulation (SBI-553-NTSR1), and covalent links.

• Degradation: Glue-E3-target ternary leads to ubiquitination, superior to bulky PROTACs in permeability.
• Gain-of-function: Restore signaling without degradation.
• Undruggable targets: Cancer (KRAS), infections, immunity.

Assays span cell-based (proximity, degradation) and biophysical (NMR, crystallography).Read the full paper.

Photo by Nigel Hoare on Unsplash

Expanding the Druggable Universe: Beyond Traditional Pockets

Only ~20% of proteome is druggable by orthosteric binders. Glues access flat PPIs, enabling E3 recruitment for degradation of 'undruggables' like transcription factors. Singapore's EDDC exemplifies this, with tools for HTS, DELs, and AI screening tailored for glues.

Recent EDDC collaborations on degraders for autoimmune diseases highlight translational impact.

Singapore's Biotech Ascendancy: A*STAR as Catalyst

A*STAR, via EDDC, positions Singapore as Asia's drug discovery hub. Capabilities include hit identification to IND, partnering academia-industry. Biotech investments surged, with RIE2030 prioritizing high-impact R&D. Molecular glues align with precision medicine goals, attracting talent and firms.

IMCB's Shuang Liu also pioneers glue discovery for neurodegeneration, amplifying efforts.

Challenges and Rational Strategies: HTS to AI

Discovery hurdles: Need PPI-focused libraries, sensitive assays. Rational tools: DELs (billions screened), fragments, in silico for interfaces. A*STAR's computational-structural synergy exemplifies.

Clinical Horizons: From Bench to Bedside

IMiDs like lenalidomide validate clinically. Pipeline includes RMC-6236 (KRAS), zoldonrasib. Singapore accelerates via EDDC's Phase 1 support, e.g., ETC-159 (Wnt inhibitor).Learn more about EDDC.

Photo by Google DeepMind on Unsplash

Future Outlook: Singapore Leading Glue Revolution

This paper charts a roadmap: Integrate multi-omics, AI for prediction. Singapore's ecosystem—talent, funding, partnerships—poises A*STAR for leadership. Expect glues tackling neurodegeneration, rare diseases.

Implications for Global Health and Singapore's Economy

Glues could transform oncology, immunity. For Singapore, bolsters biotech GDP contribution, jobs in R&D. Explore opportunities at research jobs.