In the intricate dance of cellular life, physical closeness is everything. Scientists are now learning the steps to this dance, directing partners to come together and create new moves that can heal.
For over a century, modern medicine has largely operated on a "lock and key" model. Most medicines are designed to find a specific protein target—a lock—and block or activate it by fitting perfectly, like a key. While powerful, this approach has a significant limitation: it can only address the 15-20% of human proteins that have these accessible "locks" 1 .
The vast majority of disease-causing proteins have been considered "undruggable," eluding traditional treatments. But what if we could stop trying to pick these cellular locks and instead send in a demolition crew? This is the promise of chemically induced proximity (CIP)—a revolutionary approach that uses small molecules as "molecular matchmakers" to bring cellular machines directly to disease-causing proteins, neutralizing targets once thought untreatable 1 .
Lock and key model targeting only 15-20% of proteins
Molecular matchmaking for previously undruggable targets
At its core, chemically induced proximity is a simple but powerful concept: using small molecules to bring two or more cellular components physically close together to trigger a specific biological event 3 .
Think of it as cellular matchmaking. Where traditional drugs work like a key in a lock, CIP medicines work like a host at a party, intentionally introducing two people who need to meet. One end of the CIP molecule binds to a disease-causing protein, the other end binds to an effector protein, and by bringing them together, the effector can get to work 1 .
Depending on the effector chosen, the target protein can be destroyed, inactivated, relocated, or even activated 1 3 .
This approach represents the fourth wave of drug discovery, building upon earlier waves of small molecules (like aspirin), rational drug design, and protein-based biologics 1 .
Scientists have developed two primary types of molecular matchmakers:
| Type | How It Works | Example Platforms | Primary Effect |
|---|---|---|---|
| Molecular Glues | Single molecule reinforcing protein interactions | IMiDs, LOCKTAC | Varies (degradation, stabilization) |
| Bifunctional Degraders | Two-ended molecule recruiting disposal machinery | PROTACs, LYTACs | Target protein degradation |
| T-Cell Engagers | Bringing immune cells to cancer cells | BiTE® | Immune-mediated cell death |
| Transcriptional Modulators | Relocating enzymes to alter gene expression | CDK-TCIPs | Gene activation or repression |
Disease Protein
+
Effector Protein
Therapeutic Effect
In 2024, a groundbreaking study published in Science demonstrated how CIP could overcome one of oncology's persistent challenges: selectively killing cancer cells without the toxic side effects of traditional treatments .
The research focused on BCL6, a protein that drives cancer growth in certain lymphomas by repressing pro-apoptotic (cell death) genes. Traditional kinase inhibitors that block transcription broadly often cause significant toxicity because they affect both healthy and cancer cells. The scientific team asked: Could we repurpose these inhibitors not to block, but to activate death pathways exclusively in cancer cells?
The researchers designed an elegant experiment using what they called CDK-Transcriptional Chemical Inducers of Proximity (CDK-TCIPs):
They created bivalent molecules linking two key components:
These CDK-TCIPs were introduced into BCL6-overexpressing diffuse large B-cell lymphoma (DLBCL) cells
The molecules physically relocated CDK9 to BCL6-bound DNA regions, overriding BCL6's repressive effects
This repositioning activated pro-apoptotic genes specifically at BCL6-regulated loci, sparing other genomic regions
| Research Tool | Function in Experiment |
|---|---|
| CDK9 Inhibitor Moiety | Binds and recruits CDK9 transcriptional kinase |
| BCL6 BTB Domain Ligand | Anchors complex to BCL6-bound DNA regions |
| BCL6-Driven DLBCL Cell Lines | Provide disease-relevant experimental model |
| Proteomic & Genomic Analyses | Measure phosphorylation changes and gene activation |
The findings were striking:
The most potent CDK-TCIPs demonstrated subnanomolar cytotoxicity—approximately 100 times more potent than simply combining traditional CDK9 and BCL6 inhibitors .
Proteomic and genomic analyses confirmed localized phosphorylation of RNA polymerase II and activation of BCL6-repressed apoptotic genes only at targeted loci .
The treatment killed BCL6-overexpressing cancer cells while theoretically minimizing effects on healthy cells, though mouse studies did show depletion of some normal germinal center B cells .
| Treatment Approach | Potency | Specificity | Mechanism |
|---|---|---|---|
| Traditional Kinase Inhibitors | Standard | Low (broad effects) | Inhibition |
| Combined CDK9 + BCL6 Inhibition | Moderate | Moderate | Dual Inhibition |
| CDK-TCIP Molecules | High (subnanomolar) | High (locus-specific) | Gain-of-Function |
Comparative Efficacy Visualization
CDK-TCIP shows significantly higher potency and specificity compared to traditional approaches
The success of approaches like CDK-TCIPs represents just one frontier in the rapidly expanding field of chemically induced proximity. Researchers are developing numerous other innovative strategies:
These bifunctional molecules attach disease-causing proteins inside cells to enzymes that tag them for delivery to the proteasome—the cell's garbage disposal system 1 .
These link unwanted proteins to the lysosome, a cellular recycling center, particularly targeting proteins found outside cells or embedded in cell membranes 1 .
These stick faulty RNA molecules—the precursors to proteins—to enzymes that cut them up, stopping harmful proteins from being made 1 .
This innovative "hold-and-kill" approach uses heterobifunctional molecules that bind both a cancer-specific protein and an essential protein. The molecule pools in cancer cells and only blocks the essential protein there, causing selective cancer cell death while sparing healthy cells 2 .
Despite the excitement, significant challenges remain. Not every target requires induced proximity, and not every proximity concept will translate into a safe, effective medicine 1 . Companies like Amgen are focusing on advancing only the most compelling opportunities where biology, pharmacology, and modality align 1 .
Chemically induced proximity represents more than just another technical advance—it fundamentally changes our relationship with cellular machinery. Instead of simply blocking or activating single proteins, we're learning to orchestrate complex cellular processes, directing the natural machinery of the cell to perform therapeutic work on our behalf.
From the first synthetic dimerizer FK1012 that activated T-cell signaling in the 1990s to today's sophisticated transcriptional redirectors and protein degraders, the field has evolved from a scientific curiosity to a therapeutic powerhouse 3 . As research continues to unfold, chemically induced proximity promises to turn previously undruggable targets into therapeutic opportunities, bringing hope to patients facing diseases that have long eluded effective treatment 1 .
The cellular dance continues, but now we're no longer mere observers—we're learning to become the choreographers.
References to be added here.