In the intricate dance of cellular life, proximity is power.
Explore the ScienceFor over a century, modern medicine has operated on a "lock and key" principle—a drug (the key) perfectly fits into a protein target (the lock) to either block or activate its function. While effective, this approach has a significant limitation: it can only target about 15-20% of human proteins—those with the right kind of "lock" or binding pocket 1 .
The remaining 80-85% of proteins, including many that drive devastating diseases, have been considered "undruggable" by conventional methods. Now, a revolutionary approach called chemically induced proximity (CIP) is breaking these constraints, transforming how we treat disease by recruiting the cell's own machinery against its worst enemies.
At its core, chemically induced proximity operates on a simple but powerful concept: instead of directly inhibiting a disease-causing protein, why not mark it for the cell's own disposal or recycling systems?
Chemical inducers of proximity (CIPs) are synthetic small molecules that act as "molecular matchmakers," bringing a disease-causing protein into close contact with cellular machinery that can neutralize it 1 2 . Think of these molecules as sophisticated forms of double-sided tape or specialized glues that physically connect targets to effectors.
CIPs bring together proteins that wouldn't normally interact
Single molecules can facilitate multiple rounds of target elimination
Access previously inaccessible disease-causing proteins
The origins of chemically induced proximity trace back to an unexpected source: immunosuppressive drugs 2 3 .
Scientists discovered that naturally occurring compounds like FK506, cyclosporine A, and rapamycin (used to prevent organ transplant rejection) worked through a proximity-based mechanism 2 3 . These molecules functioned by bringing together immunologically important proteins, effectively "hijacking" the immune system's communication networks.
This discovery led researchers to ask a fundamental question: if nature uses proximity as a regulatory mechanism, could scientists design synthetic proximity inducers for therapeutic purposes?
The first synthetic chemical inducer of proximity, FK1012, was developed as a homodimer of FK506 and provided the first evidence that proximity alone could activate signaling pathways in cells 2 .
The field of induced proximity has spawned an exciting array of therapeutic strategies, each designed for specific cellular targets and locations.
| Therapy Type | Mechanism of Action | Cellular Location | Example Approaches |
|---|---|---|---|
| PROTACs | Target proteins for proteasomal degradation | Intracellular | Amgen's platform, Cereblon-recruiters |
| Molecular Glues | Stabilize protein interactions leading to degradation | Intracellular | Lenalidomide, Pomalidomide |
| BiTEs | Engage immune cells to target cancer cells | Cell Surface | Amgen's approved cancer therapies |
| LYTACs | Target proteins for lysosomal degradation | Extracellular/Membrane | Early-stage research |
| RIBOTACs | Degrade faulty RNA precursors | Intracellular | Early-stage research |
Among the most advanced proximity-based approaches, PROTACs are heterobifunctional molecules—essentially, they have two ends connected by a chemical linker 5 . One end binds to a disease-causing protein, while the other end recruits an E3 ubiquitin ligase, an enzyme that tags proteins for destruction.
What makes PROTACs particularly exciting is their catalytic nature 5 . A single PROTAC molecule can facilitate the destruction of multiple target proteins in sequence, being released after each degradation event to seek another target.
While PROTACs are typically larger, bifunctional molecules, molecular glues represent a more minimalist approach. These are typically smaller, monovalent molecules that either enhance existing protein interactions or create new ones 3 .
The immunomodulatory drugs (IMiDs) like thalidomide and its derivatives (lenalidomide, pomalidomide) represent successful examples of molecular glues already serving patients. These drugs work by recruiting novel protein substrates to cereblon, a component of the E3 ubiquitin ligase complex, leading to their degradation 3 .
While the potential of targeted protein degradation is enormous, a significant challenge has limited its progress: the narrow set of exploitable effector proteins and ligand binding sites currently available . Most PROTACs rely on just a handful of E3 ligases, particularly cereblon and VHL, restricting the scope for improved selectivity and potentially leading to drug resistance.
To address this limitation, researchers at Imperial College London developed an innovative chemical-genetic platform called SLIP (Site-specific Ligand Incorporation-induced Proximity) . Here's how it works:
| Step | Process | Key Innovation |
|---|---|---|
| 1. Site Selection | Choose potential effector sites on E3/E2 ligases | Comprehensive screening approach |
| 2. Genetic Encoding | Incorporate unnatural amino acids via genetic code expansion | Precise positioning in live cells |
| 3. Ligand Attachment | "Click" chemistry ligation of PROTAC ligand | Covalent, site-specific conjugation |
| 4. Functional Assessment | Measure degradation of target proteins | Identifies functionally actionable sites |
The SLIP platform successfully identified multiple novel potentially "PROTACable" sites on E3 ligases and even E2 enzymes (which work with E3 ligases in the ubiquitination process) that demonstrated competence for targeted protein degradation .
Provides a universal strategy to identify new ligand binding sites on any potential effector protein
Works in live cells, accounting for the complex cellular environment
Could be adapted for other proximity-induced pharmacology mechanisms
Advancing induced proximity therapies requires specialized research tools. At the forefront are PROTAC toolkits that enable efficient synthesis and testing of potential therapeutic molecules 5 .
These toolkits typically include pre-designed components that researchers can mix and match:
| Reagent Type | Function | Examples |
|---|---|---|
| E3 Ligase Ligands | Recruit the cellular degradation machinery | Cereblon, VHL, MDM2 ligands |
| Linker Moieties | Connect target and effector ligands | Various chemical chains with different lengths and properties |
| Click Chemistry Components | Enable efficient molecule assembly | Azide-functionalized linker moieties, alkyne-equipped target ligands |
| Target Protein Ligands | Bind to disease-causing proteins | Kinase inhibitors, receptor binders |
The University of Ghent's Medicinal Chemistry laboratory, for instance, has developed a toolkit that combines E3-ligase ligands and linker moieties in single molecules, with terminal ends pre-equipped with azide functional groups 5 . When researchers want to target a specific protein, they simply equip a known ligand for that protein with a terminal alkyne and use a copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction—a type of "click" chemistry—to connect the pieces 5 .
The implications of chemically induced proximity for patient care are profound. This approach has the potential to unlock treatment for conditions that currently lack effective therapies by targeting previously "undruggable" proteins 1 .
Amgen already has two approved bispecific T-cell engager (BiTE®) molecules in oncology that work through induced proximity 1 . These medicines bring tumor cells and immune T cells together, enabling the immune system to attack the cancer without requiring a traditional binding pocket on the cancer cell.
The catalytic, reusable nature of many proximity-based therapies means they could deliver lasting benefits with smaller doses 1 . Because one molecule can eliminate multiple target proteins in sequence, the therapeutic effect may extend beyond the drug's presence in the body.
Despite the excitement, significant challenges remain. As one researcher notes, "Not every target requires induced proximity, and not every proximity concept will translate into a safe, effective medicine" 1 . The strategic focus is on advancing only the most compelling opportunities where biology, pharmacology, and modality align 1 .
Approaches like RIPTACs (regulated induced proximity targeting chimeras) aim to create cancer-selective therapies that only affect diseased cells 3 .
Technologies like SELFTAC (which splits PROTACs into smaller molecules) and hypoxia-activated PROTACs aim to improve drug delivery and specificity 3 .
The field continues to accelerate, with significant investment and a growing number of companies (approximately 90 by some counts) dedicated to exploiting these approaches 3 . The 5th Annual Induced Proximity-Based Drug Discovery Summit in 2025 highlighted cutting-edge research on RIPTACs, DUBTACs, RIBOTACs, and other novel modalities 4 .
Chemically induced proximity represents a fundamental shift in therapeutic philosophy—from inhibiting specific protein functions to rewiring cellular networks by harnessing the cell's own machinery.
What makes this approach particularly powerful is how it mirrors nature's own regulatory mechanisms. Cells have always used proximity as a control mechanism; scientists are now learning the rules of this molecular dance and developing tools to direct it. As research progresses, chemically induced proximity may well unlock a new generation of transformative therapies, bringing hope to patients facing diseases that currently lack effective treatment options.
The molecular matchmakers have arrived—and they're bringing previously undruggable targets within reach.