Induced Proximity: Turning Molecular Matchmakers into Medicines

What is Amgen's Induced Proximity Platform (IPP)?

Most medicines today work like a key fitting into a lock, which limits their reach to proteins with the right kind of lock, or binding pocket. Only about 15-20% of human proteins fall into that category. Amgen's Induced Proximity Platform (IPP) takes a different approach. Instead of relying on direct binding, these medicines bring a disease-causing protein into proximity with a cellular machine that can neutralize it. This expands the possibilities of what can be targeted and treated.

How does IPP fit into the bigger picture of drug discovery?

Drug discovery has evolved in waves:

• The early 1900s saw the first wave with small molecules like aspirin, where scientists understood the chemistry but not the biology of how these medicines work in the body.
• The 1970s brought the second wave that included rational drug design of known small molecules with known targets.
• The 1980s led the third wave that included the rise of biologics, or protein-based medicines, which defined Amgen's early success.
• Now is the fourth wave that includes the design of induced-proximity medicines. Rather than blocking a target directly, these medicines use the cell's own machinery to degrade, silence or reprogram disease drivers.

Building on four decades of advancing biologic medicines, Amgen is now applying the same spirit of innovation to unlock this next frontier in drug discovery and development.

How does induced proximity work?

Think of induced proximity medicines as molecular matchmakers. One end binds to the target protein, the other binds to an effector protein, and the two are brought together so the effector can do the work. Depending on the effector chosen, the target protein can be destroyed, inactivated, relocated or even activated. This design principle can be applied using small molecules, biologics (such as antibodies) or hybrid approaches.

Amgen scientists have built libraries of chemical "keys," or molecules, that can be tested across nearly every "door," or target, in the human body at once - speeding discovery and finding connections that would otherwise remain hidden.

What are examples of induced proximity molecules?

Some induced proximity therapies are already serving patients. Amgen has two approved bispecific T-cell-engager, or BiTE^® molecules, in Oncology that bring tumor cells and immune T cells together so the immune system can attack the cancer. These medicines don't require a traditional binding pocket; they use proximity to trigger their effect.

Amgen researchers are also exploring other proximity approaches such as LOCKTAC molecular glues that are designed to target disease processes by stabilizing existing cellular interactions.

Other potential induced proximity strategies include:

• Protein glues (e.g. PROTACs - Proteolysis Targeting Chimeras): These act like double-sided tape, attaching a disease-causing protein to an enzyme that tags it for delivery to the proteasome - the cell's garbage disposal system - so it gets broken down. Disease proteins targeted by protein glues are found inside the cell.
• Cell-surface glues (e.g. LYTACs - Lysosome Targeting Chimeras): These link unwanted proteins to the lysosome, a type of recycling center in the cell. Disease proteins targeted by these glues are typically found outside of the cell or embedded in a cell membrane.
• RNA glues (e.g. RNATACs - RNA-Targeting Chimeras): These stick faulty RNA molecules - the precursors to proteins - located within the cell to enzymes that cut them up, stopping harmful proteins from being made.

How is Amgen building the Induced Proximity Platform (IPP)?

Amgen has invested in multiple ways to discover and develop induced proximity medicines:

• DNA-encoded libraries (DEL): Amgen's powerful platform uses DNA tags to barcode individual chemical compounds in huge mixtures. Scientists then screen these vast numbers of molecules across targets with the highest disease-driving potential to identify promising proximity inducers.
• External partnerships: Amgen is collaborating with external companies to explore programs that include targeted RNA degraders and molecular glues.
• Disciplined focus: Induced proximity is only applied where it makes the most biological and clinical sense. This targeted approach has evolved as Amgen scientists have learned more about the biology and chemistry of multispecific medicines.

By integrating its IPP with other key platforms across the company, Amgen is bringing innovation at scale across the Research pipeline.

Why does this matter for patients?

Induced proximity has the potential to unlock a vast portion of the disease targets that were once thought unreachable. By removing or silencing disease drivers, these medicines may deliver deeper, more durable responses than traditional inhibitors, which often bind targets in a more transient way. Because the mechanism is reusable - one molecule can eliminate multiple target proteins in sequence - the approach could also deliver lasting benefits with smaller doses.

What challenges remain?

Not every target requires induced proximity, and not every proximity concept will translate into a safe, effective medicine. Amgen's strategy is to advance only the most compelling opportunities, where the biology, pharmacology and modality align, to ensure that patients benefit from the science.

Induced proximity is expanding what medicines can do by recruiting the cell's own machinery against disease. This platform is one way Amgen is working to turn a powerful design principle into the next generation of transformative therapies with the potential to help patients in need.