Induced proximity is a therapeutic strategy in which small molecules are designed to bring two proteins into proximity to produce a biological effect that conventional inhibitors cannot. The approach includes several modalities—most prominently PROTACs (proteolysis-targeting chimaeras), molecular glues and newer formats such as RIPTACs—that exploit engineered protein–protein interactions to destroy, stabilize or otherwise rewire cellular machinery.
The concept dates back more than two decades to work by Craig Crews and colleagues, who proposed that small molecules could be used to recruit a target protein to the cell’s degradation machinery, enabling its selective removal rather than simple inhibition.
PROTACs are bifunctional molecules with two binding domains: one that engages a disease-associated protein and another that recruits an element of the ubiquitin–proteasome degradation system. Formation of the ternary complex marks the target for destruction, which can abrogate protein function more completely than occupancy-based blockade.
Craig Crews, a pioneer in the field and co-founder of companies pursuing induced-proximity platforms, emphasizes that the ability to force interactions between proteins that did not evolve to bind each other opened a wide range of therapeutic possibilities beyond degradation alone.
A landmark for the field came in 2026 when the US Food and Drug Administration approved the oral PROTAC degrader vepdegestrant (Veppanu), developed by Arvinas and Pfizer, for estrogen receptor-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. In phase 3 testing, vepdegestrant improved progression-free survival relative to fulvestrant, reducing the risk of disease progression or death by 43% in the reported study.
This approval provided important validation for the induced-proximity paradigm, easing concerns in industry and encouraging more high-risk, high-reward programs to advance into clinical development.
More than 30 PROTAC therapeutics are under clinical evaluation. Oncology remains a dominant area, with programs targeting androgen receptor degraders in prostate cancer and degraders aimed at overcoming resistance in B cell malignancies. Examples in the clinical pipeline include Bristol Myers Squibb’s phase 3 study of gridegalutamide in metastatic castration-resistant prostate cancer and BeOne Medicines’ phase 3 program for BGB-16673 in B cell malignancies.
Induced proximity is also moving beyond oncology. The FDA granted Fast Track designation in April 2025 to Kymera Therapeutics’ degrader KT-621 for moderate to severe eosinophilic asthma. Arvinas and other groups are exploring degraders for neurodegenerative diseases such as Parkinson’s disease.
Molecular glues are small molecules that directly induce an interaction between two proteins—acting as biological adhesives—rather than recruiting a target to the ubiquitin machinery. Some historically important drugs, such as members of the thalidomide family, were later found to function as molecular glues, and most known glues were discovered serendipitously.
Efforts are now underway to discover molecular glues more deliberately. New companies and programs aim to move beyond chance discovery. For example, Craig Crews launched Quarry Thera in 2025 to focus on rational glue discovery. Bristol Myers Squibb has molecular-glue candidates such as mezigdomide in clinical development for refractory multiple myeloma. Amgen is developing a related concept called LOCKTACs, designed to ‘lock’ two interacting molecules together to prolong their interaction; an example is anvumetostat (AMG 193), a LOCKTAC-stage candidate intended to inhibit PRMT5 in certain advanced thoracic tumors.
Regulated induced proximity-targeting chimeras, or RIPTACs, represent an ambitious extension of induced-proximity strategies. Rather than recruiting a target to degradation, RIPTACs create a new, lethal interaction inside cancer cells by linking a tumor-enriched protein to an essential cellular regulator. The approach exploits differential protein abundance between tumor and healthy tissue: a protein that is highly expressed in tumor cells becomes the handle used to tether an essential effector, disabling its function selectively in cancer cells.
RIPTACs are therefore not necessarily aimed at classical oncogenic drivers; instead, they leverage proteins that are selectively abundant in tumors to generate a cytotoxic or cytostatic effect when connected to an essential regulator.
Commercial and academic programs are advancing RIPTACs into clinical testing. Halda Therapeutics, a Yale University spinout, developed a RIPTAC program in which lead product HLD-0915 links the androgen receptor (often overexpressed in prostate tumors) to BRD4, an essential regulator for cancer cell survival. In October 2025 Halda reported early phase 1/2 results indicating that 59% of patients who received at least six weeks of HLD-0915 achieved a PSA50 response, while 32% achieved a PSA90 response. HLD-0915 received FDA Fast Track designation in August 2025.
The commercial interest in RIPTACs was underscored when Johnson & Johnson acquired Halda Therapeutics for US$3.05 billion in November 2025, citing promising early data and the platform’s potential to overcome resistance in the androgen receptor pathway.
Beyond RIPTACs, the broader induced-proximity field includes multiple late-stage and early-stage clinical programs addressing resistance mutations, alternative cancer types and non-oncology indications.
Key challenges remain in the induced-proximity field. For molecular glues, most known examples were discovered by chance, and rational discovery methods are still emerging. For PROTACs and RIPTACs, designing effective ternary complexes that form selectively in diseased tissue, predicting off-target effects, and managing pharmacology distinct from traditional inhibition are ongoing hurdles.
Nevertheless, industry and academic leaders described the FDA approval of a PROTAC and the early RIPTAC clinical signals as catalytic. The approval has reduced regulatory uncertainty, and the diversity of proximity-based approaches—degraders, glues, LOCKTACs and RIPTACs—is expanding the target space accessible to drug developers and offering new strategies to address drug resistance and previously intractable targets.
The field is now characterized by an increasing number of clinical programs, cross-company investment, and deliberate efforts to develop rational discovery platforms for molecular glues and other proximity modalities. These developments suggest that induced proximity is maturing into a broad therapeutic paradigm with applications in oncology and beyond.