---
title: "Induced proximity therapies: PROTACs, molecular glues and RIPTACs in oncology"
id: "nature-3-induced-proximity-comes-of-age"
canonical_url: "https://medichelpline.com/clinical-feed/nature-3-induced-proximity-comes-of-age"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "Nature Medicine"
source_url: "https://www.nature.com/articles/d41591-026-00045-z"
published_at: "2026-09-03T12:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Induced proximity therapies: PROTACs, molecular glues and RIPTACs in oncology
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/nature-3-induced-proximity-comes-of-age
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** Nature Medicine
- **Source URL:** [Original Journal Publication](https://www.nature.com/articles/d41591-026-00045-z)
- **Published At:** 2026-09-03T12:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- Induced proximity is a therapeutic paradigm in which small molecules force new protein–protein interactions to achieve effects beyond conventional inhibition; examples include **PROTACs**, molecular glues and **RIPTACs**. - PROTACs use bifunctional molecules to recruit a target protein to the cell’s degradation machinery, enabling selective destruction rather than inhibition. The concept originated with Craig Crews more than two decades ago. - Regulatory validation arrived in 2026 with FDA approval of the oral estrogen receptor degrader **vepdegestrant (Veppanu)** for ER-positive, HER2-negative, ESR1-mutated advanced breast cancer; phase 3 testing showed a 43% reduction in risk of progression or death versus fulvestrant. - More than 30 PROTAC candidates are in clinical trials, spanning oncology (androgen receptor degraders in prostate cancer; B cell malignancies) and non-oncology indications (eosinophilic asthma; neurodegenerative disease programs). - Molecular glues—small molecules that directly induce protein–protein interactions—were historically discovered serendipitously (e.g., thalidomide family). Companies now pursue rational discovery of glues, including Quarry Thera, Bristol Myers Squibb and Amgen’s LOCKTAC class. - **RIPTACs** are an ambitious extension that link a tumor-enriched protein to an essential regulator to create a lethal ternary complex; they exploit differential protein abundance rather than canonical oncogenic drivers. - Johnson & Johnson acquired Halda Therapeutics for US$3.05 billion after Halda’s RIPTAC platform advanced HLD-0915 into clinical trials for metastatic castration-resistant prostate cancer; HLD-0915 links androgen receptor to BRD4. - Early phase 1/2 data for HLD-0915 reported a PSA50 response in 59% of patients treated at least six weeks and PSA90 in 32%; HLD-0915 received FDA Fast Track designation in August 2025. - The induced-proximity field is diversifying target space and pharmacology, offering routes to overcome resistance mutations, but discovery challenges remain—particularly in rationally finding molecular glues and designing effective ternary complexes. - The FDA approval of a PROTAC and emerging clinical data for RIPTACs and other proximity modalities are catalyzing investment and new high-risk, high-reward development programs across industry and academia.
## Clinical Analysis & Structured Key Points
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[nature](https://www.nature.com/) 2. [nature medicine](https://www.nature.com/nm) 3. [news](https://www.nature.com/nm/articles?type=news) 4. article * NEWS * 03 September 2026 # Induced proximity comes of age The first approved PROTAC for breast cancer validated the idea that medicines can work by bringing proteins together rather than by simply blocking them. Now, a new generation of proximity-based therapies is pushing that principle further. By * [ Natalie Healey](https://www.nature.com/articles/d41591-026-00045-z#author-0)[0](https://www.nature.com/articles/d41591-026-00045-z#Aff0) 1. Natalie Healey 1. Natalie Healey is a freelance writer in London, UK. [View author publications](https://www.nature.com/search?author=Natalie+Healey) Search author on: [PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Natalie+Healey) [Google Scholar](https://scholar.google.co.uk/scholar?as_q=&btnG=Search+Scholar&as_sauthors=%22Natalie%2BHealey%22) * Email * [ Bluesky ](https://bsky.app/intent/compose?text=Induced+proximity+comes+of+age%20https%3A%2F%2Fwww.nature.com%2Farticles%2Fd41591-026-00045-z) * [ Facebook ](https://www.facebook.com/sharer.php?u=https%3A%2F%2Fwww.nature.com%2Farticles%2Fd41591-026-00045-z&t=Induced+proximity+comes+of+age) * [ LinkedIn ](https://www.linkedin.com/shareArticle?text=Induced+proximity+comes+of+age&url=https%3A%2F%2Fwww.nature.com%2Farticles%2Fd41591-026-00045-z) * [ Reddit ](https://www.reddit.com/submit?title=Induced+proximity+comes+of+age&url=https%3A%2F%2Fwww.nature.com%2Farticles%2Fd41591-026-00045-z) * [ Whatsapp ](https://wa.me/?text=Induced+proximity+comes+of+age%20https%3A%2F%2Fwww.nature.com%2Farticles%2Fd41591-026-00045-z) * [ X ](https://twitter.com/intent/tweet?text=Induced+proximity+comes+of+age&url=https%3A%2F%2Fwww.nature.com%2Farticles%2Fd41591-026-00045-z) [ Save article ](https://www.nature.com/articles/d41591-026-00045-z/save-research?_csrf=LujqG-QJftugORqdiV0WyvupjDb2AyDo) [ View saved research ](https://www.nature.com/saved-research) ![](https://media.nature.com/lw767/magazine-assets/d41591-026-00045-z/d41591-026-00045-z_50850336.jpg) Image credit: Denis Pobytov / DigitalVision Vectors / Getty When Johnson & Johnson acquired Yale University spinout [Halda Therapeutics for US $3.05 billion](https://ventures.yale.edu/news/yale-spinout-halda-therapeutics-announces-3b-acquisition-johnson-johnson) in November 2025, it was making a bet on a therapeutic platform with no approved drugs and only one early-stage clinical trial. Halda’s lead asset had just entered trials in prostate cancer, but its approach, called regulated induced proximity-targeting chimeras (RIPTACs), represented a potential solution to one of oncology’s biggest challenges. “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. We’d never seen anything quite like that.” RIPTACs are one branch of a broader therapeutic concept known as induced proximity, in which medicines engineer protein–protein interactions to create biological effects that conventional drugs cannot achieve. **Come together** The idea that drugs could be designed to destroy proteins rather than merely inhibit them was first proposed by pharmacologist Craig Crews at Yale University more than [two decades ago](https://www.pnas.org/doi/10.1073/pnas.141230798). PROTACs (proteolysis-targeting chimaeras) use a bifunctional molecule with two binding regions. One attaches to a disease-causing protein, while the other recruits the cell’s natural degradation machinery. The resulting complex marks the target for destruction, disabling the protein entirely. “The thing we learned was that we could bring together two proteins that had not evolved to bind to one another,” says Crews, co-founder of Halda and biotechnology company Arvinas. “That opened up the possibility of using induced proximity in many different ways.” That concept reached a major milestone in 2026 when vepdegestrant (Veppanu), an oral estrogen receptor degrader developed by Arvinas and Pfizer,[ became the first PROTAC to receive regulatory approval](https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-vepdegestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast) from the US Food and Drug Administration (FDA). Vepdegestrant is approved for patients with estrogen receptor-positive, HER2-negative, _ESR1_ -mutated advanced breast cancer. In [phase 3](https://www.nejm.org/doi/abs/10.1056/NEJMoa2505725) testing, the therapy improved progression-free survival relative to the cancer drug fulvestrant, reducing the risk of disease progression or death by 43%. For researchers developing next-generation proximity medicines, the approval provides important validation. “People would get nervous when you said ‘PROTAC’ because there wasn’t an FDA-approved one,” says George Burslem, a biochemist at the University of Pennsylvania. “I hope that approval will relieve some of that concern, and that we’ll start seeing more high-risk, high-reward programs come through.” “I think induced proximity is becoming a genuine therapeutic paradigm,” says Ryan Potts, vice president of research at Amgen. “You’re accessing a very different target space than traditional inhibitors, and a very different kind of pharmacology.” **A clinical proving ground** More than [30 PROTAC](https://pmc.ncbi.nlm.nih.gov/articles/PMC12473374/) therapeutics are now being evaluated in clinical trials. In prostate cancer, androgen receptor degraders are being developed to overcome resistance to androgen-signaling inhibitors. Bristol Myers Squibb’s phase 3 study is evaluating gridegalutamide ([NCT06764485](https://clinicaltrials.gov/study/NCT06764485)) in metastatic castration-resistant prostate cancer. Hematological malignancies represent another major area of activity. BeOne Medicines’ phase 3 study for BGB-16673 ([NCT06846671](https://clinicaltrials.gov/study/NCT06846671)) aims to overcome resistance mutations that limit current therapies for B cell malignancies. The approach is also beginning to move beyond oncology. In April 2025, the FDA granted Fast Track designation to the [Kymera Therapeutics](https://investors.kymeratx.com/news-releases/news-release-details/kymera-therapeutics-announces-us-fda-fast-track-designation-kt-0) degrader KT-621 for the treatment of moderate to severe eosinophilic asthma. Arvinas is also exploring PROTAC approaches for neurodegenerative diseases [such as Parkinson’s disease](https://euclinicaltrials.eu/search-for-clinical-trials/?lang=en&EUCT=2024-516888-84-00). For Crews, degradation was only the beginning. “We found out that we could take any two proteins and bring them together for other purposes,” he says. “Because we could do this over and over, we realized we weren't limited to degradation.” **Stick it out** Some of the earliest examples of induced proximity were hiding in plain sight: thalidomide and related immunomodulatory drugs were later found to [act as molecular glues](https://pmc.ncbi.nlm.nih.gov/articles/PMC9910052/)—small molecules that behave as biological adhesives, forcing two proteins to bind together that normally would not interact. Unlike PROTACs, which typically recruit a target protein to the cell’s degradation machinery, molecular glues induce an interaction directly between two proteins. “Nearly all of the molecular glues we know about were discovered by serendipity,” says Burslem. “The challenge is how you find them in a more rational way.” That challenge is now attracting new approaches. Crews’ latest company, [Quarry Thera](https://www.quarrythera.com/), launched in 2025 with former Pfizer chief scientific officer Mikael Dolsten, is focused on discovering molecular glues deliberately. Bristol Myers Squibb has several molecular glue candidates (such as mezigdomide for refractory multiple myeloma) in clinical development. Amgen is investigating a class of therapeutic candidates it calls LOCKTACs. These molecules are designed to act as a type of [molecular glue](https://pubmed.ncbi.nlm.nih.gov/40839737/) that ‘locks’ two naturally interacting molecules together and holds them in place for longer than they would bind on their own. The company’s product anvumetostat ([AMG 193](https://clinicaltrials.gov/study/NCT06333951)) is a clinical-stage LOCKTAC molecule designed to inhibit the enzyme PRMT5 in certain cancer cells, such as those in advanced thoracic tumors. **RIP up the playbook** RIPTACs represent one of the most ambitious extensions of induced proximity. Rather than degrading a target protein, they use proximity to create a new, lethal interaction inside cancer cells. The strategy relies on a feature that distinguishes many tumors from healthy tissue: abnormal levels of certain proteins. RIPTACs exploit these differences by [linking](https://www.cell.com/cell-chemical-biology/fulltext/S2451-9456\(24\)00307-6) a cancer-associated protein to an essential cellular regulator, disabling a process the tumor depends on. Unlike conventional targeted therapies, which often focus on proteins that drive cancer growth, RIPTACs exploit proteins that are not themselves disease drivers but are selectively abundant in tumor cells. “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](https://utswmed.org/doctors/adeel-khan/) at UT Southwestern Medical Center. The resulting complex prevents the regulatory protein from functioning, effectively stopping cancer cell growth while sparing healthy cells that lack sufficient levels of the tumor-associated protein. “As long as you have a protein that’s highly expressed in a tumor relative to healthy tissue, and design the right ternary complex, there’s an opportunity to apply this more broadly,” says Tillyer. Halda’s lead product, HLD-0915, is being evaluated in metastatic castration-resistant prostate cancer, with a second product that targets estrogen receptor-positive breast cancer also entering clinical development. In prostate cancer, tumor cells often have high expresson of the androgen receptor. Halda’s HLD-0915 links the androgen receptor to BRD4, a protein required for the survival of cancer cells. The resulting complex disables BRD4 and selectively kills androgen receptor-expressing tumor cells. Early clinical phase 1/2 data suggest that the approach may be effective even in heavily pretreated disease. In October 2025, [Halda reported](https://www.mdanderson.org/newsroom/research-newsroom/new-oral-therapy-shows-early-signs-of-safety-and-effectiveness-i.h00-159780390.html) that 59% of patients who received at least 6 weeks of HLD-0915 achieved a PSA50 response (a drop in prostate-specific antigen levels of at least 50% from baseline), while 32% achieved a PSA90 response. The product received [Fast Track designation](https://ventures.yale.edu/news/halda-therapeutics-receives-fda-fast-track-designation-hld-0915-treatment-metastatic) from the FDA in August 2025. **Resisting resistance** ## Enjoying our latest content? 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