Induced Proximity Therapies Gain Ground After First PROTAC
The first FDA-approved PROTAC drug for breast cancer has validated a new class of medicines that work by bringing proteins together.
The first PROTAC drug for breast cancer has received U.S. Regulatory approval, validating a therapeutic approach based on forcing proteins to interact. This milestone for induced proximity medicines is now fueling a wave of next-generation clinical programs targeting cancer resistance and other diseases.
Johnson & Johnson acquired Yale University spinout Halda Therapeutics for $3.05 billion in November 2025, betting on its early-stage regulated induced proximity-targeting chimeras (RIPTACs) platform. Halda's lead asset had just entered trials for prostate cancer. "For years, we'd been looking for compounds that could overcome resistant variants in the androgen receptor pathway," says Richard Tillyer, global head of discovery, product development and supply at Johnson & Johnson. "Halda showed us early data that they could actually kill these highly resistant cancers."
A New Therapeutic Paradigm
The core concept of induced proximity involves designing medicines to engineer protein-protein interactions, creating biological effects conventional drugs cannot achieve. The idea that drugs could destroy proteins rather than just inhibit them was first proposed by Yale pharmacologist Craig Crews over two decades ago. This led to PROTACs (proteolysis-targeting chimaeras), which use a bifunctional molecule to tag a disease-causing protein for destruction by the cell's natural machinery.
"The thing we learned was that we could bring together two proteins that had not evolved to bind to one another," says Crews, a co-founder of Halda and Arvinas. "That opened up the possibility of using induced proximity in many different ways." The concept reached a major milestone in 2026 when vepdegestrant (Veppanu), an oral estrogen receptor degrader from Arvinas and Pfizer, became the first FDA-approved PROTAC. It is approved for patients with estrogen receptor-positive, HER2-negative, ESR1-mutated advanced breast cancer. In phase 3 testing, it improved progression-free survival relative to fulvestrant, reducing the risk of disease progression or death by 43%.
The Expanding Clinical Landscape
More than 30 PROTAC therapeutics are now in clinical trials. The field is expanding beyond oncology, though cancer remains a major focus. Key ongoing trials include programs for prostate cancer and blood cancers.
| Company | Drug Candidate | Target Condition | Trial Phase |
|---|---|---|---|
| Bristol Myers Squibb | gridegalutamide | Metastatic castration-resistant prostate cancer | Phase 3 |
| BeOne Medicines | BGB-16673 | B cell malignancies | Phase 3 |
In April 2025, the FDA granted Fast Track designation to Kymera Therapeutics' degrader KT-621 for moderate to severe eosinophilic asthma. Arvinas is also exploring PROTAC approaches for neurodegenerative diseases like Parkinson's.
Beyond Degradation: Molecular Glues and RIPTACs
Researchers are exploring induced proximity for purposes beyond protein degradation. Some of the earliest examples were discovered accidentally, such as thalidomide and related immunomodulatory drugs, which act as 'molecular glues.' These small molecules force two proteins to bind together. "Nearly all of the molecular glues we know about were discovered by serendipity," says George Burslem, a biochemist at the University of Pennsylvania. "The challenge is how you find them in a more rational way." New companies like Quarry Thera, launched in 2025 by Crews and former Pfizer CSO Mikael Dolsten, aim to discover molecular glues deliberately. Large firms are also active: Bristol Myers Squibb has candidates like mezigdomide for multiple myeloma, and Amgen is developing LOCKTACs, designed to lock naturally interacting molecules together longer.
RIPTACs represent an ambitious extension. Rather than degrading a target, they use proximity to create a new, lethal interaction inside cancer cells. They exploit proteins that are overexpressed in tumors but not in healthy tissue. "RIPTACs act as 'handcuffs' that bind an overexpressed cancer-specific protein to an essential effector or regulatory protein required for cell growth and replication," explains oncologist Adeel Khan at UT Southwestern Medical Center. This disables the essential protein, stopping cancer cell growth while sparing healthy cells.
Halda's lead product, HLD-0915, links the overexpressed androgen receptor in prostate cancer to the essential protein BRD4. Early phase 1/2 data reported in October 2025 showed that 59% of patients receiving at least six weeks of HLD-0915 achieved a PSA50 response, with 32% achieving a PSA90 response. The product received FDA Fast Track designation in August 2025. A second RIPTAC targeting estrogen receptor-positive breast cancer is also entering clinical development.
