The cell membrane is notoriously selective about what it lets in. Charged molecules? Mostly rejected at the door. That’s a problem, because some of the most promising drug targets sit behind that barrier, and reaching them requires chemistry the membrane won’t tolerate.
Continue reading “Charged Molecular Glues: The Molecular Trojan Horse That Slipped Past Biology’s Toughest Bouncer “Protein degrader research has yielded its first approved therapeutic for specific breast cancer patients: Vepdegestrant received FDA approval on May 1, 2026 (1). Vepdegestrant is an oral PROteolysis TArgeting Chimera (PROTAC) that targets the estrogen receptor for degradation in breast cancer patients with ESR1-mutated ER+/HER2– advanced breast cancer (2) produced by Arvinas, Inc. in collaboration with Pfizer Inc.
Targeted protein degraders (or PROTACs) have opened new possibilities in drug discovery research. Instead of inhibiting protein function or interaction, degraders cause the removal of the target protein itself. Traditional small molecule drugs work by binding a protein to inhibit it or block function, and they must remain bound to work. That means that the target protein should be well-characterized in terms of binding and activity sites, and the drug must bind specifically only to the target protein. In contrast, degraders only need to bind long enough to recruit cellular protein degradation machinery to the target protein, and the method does not rely on an accessible and specific binding site on the target protein. Once degradation occurs, the degrader is released and can engage with the next target.
The approval of vepdegestrant is a landmark moment for the entire TPD and induced proximity field, demonstrating that it is possible to rationally design molecules whose pharmacology is categorically distinct from traditional drugs, relying on a catalytic rather than occupancy-driven mechanism of action. More importantly, this translates to meaningful clinical outcomes in patients. —Dr. Kristin Riching, Promega R&D Scientist
The first peptide-based PROTAC was described in 2001 in the laboratories of Craig Crews and Ray Deshaies (3), but translating the concept into orally bioavailable, clinically viable molecules took nearly two decades, using tools that did not exist when the field began. More than 40 PROTAC degraders have now entered clinical trials (4), with vepdegestrant the most advanced, supported by Phase 3 data from the VERITAC-2 trial demonstrating statistically significant improvement in progression-free survival in ESR1-mutant patients. That progress required solving a measurement problem as much as a chemistry one: how do you quantify target protein degradation at endogenous levels, with enough sensitivity and throughput to drive a screening campaign? CRISPR-engineered protein tagging combined with the small bioluminescent reporter tag, HiBiT solved that problem, providing a sensitive, HTS-compatible readout of endogenous target levels without relying on laborious, artifact-prone western blots. Critically, HiBiT also enabled researchers to watch target protein degradation unfold in real time in living cells.
“Seeing it happen in real time, frankly, may have been what convinced many people that the modality had genuine merit.”
—Dr. Kristin Riching
Developing a PROTAC is not like developing a traditional inhibitor. Success requires successful completion of a complex cascade of cellular events: the molecule must enter the cell, engage the target protein and the E3 ligase simultaneously, form a productive ternary complex in the right geometry, trigger ubiquitination, and drive proteasomal degradation, all while competing with cellular noise that can blunt each step. “PROTACs are large molecules, so they are often not very permeable,” Riching explains. “They also need to simultaneously engage both the target and the E3 ligase machinery, but they need to do so in a productive geometry that leads to ubiquitination, which is not easily predicted. In cells, many compounding factors can limit activity, making it difficult to identify which parameters most need improvement. Event-driven modalities like PROTACs rely on robust tools to tease apart each mechanistic step to aid SAR optimization.”
Getting that data means adopting a screening framework built around mechanistic understanding of the full degradation cascade from the earliest stages of optimization, while preserving the native biology and the stoichiometric relationships that govern degradation efficiency. It also means going beyond endpoint measurements. Knowing whether a target is degraded is a starting point; knowing how fast, how completely, and how durably it degrades is what distinguishes a development candidate from a dead end. Riching’s research has shown that different proteins in the same family can respond to the same PROTAC with dramatically different kinetic profiles (5,6), which is a distinction that endpoint assays cannot capture, and one that can determine which compounds are worth advancing.
The approval of Vepdegestrant validates more than just a single drug, it validates the PROTAC drug category and the tools and methods that enabled it. For researchers working on next-generation degraders, the signal is clear: the modality works. Now the question is how far we can push it.
Riching points to E3 ligase diversity as the field’s most pressing unresolved problem. “The greatest challenge will be expanding beyond the two E3 ligases — CRBN and VHL — that have driven most PROTAC progress to date,” she says. “We don’t yet fully understand the scope of targets accessible through these ligases, but it stands to reason that additional ligases will be necessary to unlock a larger portion of the degradable proteome. Their broad distribution also limits opportunity for tissue-selective targeting. Developing the tools and chemistry to recruit a wider repertoire of E3 ligases remains one of the most important unsolved problems the field faces.”
Beyond ligase diversity, the field is expanding its conception of what a degrader can be. Molecular glues, LYTACs, and other induced proximity strategies are broadening the range of accessible targets — including extracellular and membrane-bound proteins that sit outside the reach of classical PROTACs. Each new modality brings its own characterization challenges, and the same principle holds: understanding mechanism at the cellular level, early and rigorously, is what separates the compounds worth advancing from those that look promising in a tube.
The approval of vepdegestrant is a landmark. But researchers working in this space know it is a beginning as much as it is a culmination — proof that the approach is sound, and a starting line for everything that follows.
Read more about Innovative Imaging Solutions for Targeted Protein Degradation on our website.
This article was written with AI assistance.
Earlier this fall, more than 90 researchers from academia and industry gathered at the Promega Madison campus for the 4th TPD & Induced Proximity Symposium. The event focused on the rapidly advancing field of targeted protein degradation (TPD) and the broader concept of induced proximity—therapeutic strategies that bring two or more proteins into proximity to trigger a specific biological effect.
This 4th year reflected of the symposium a maturing and diversifying field with chemoproteomics and proteomescale mapping redefining what it means to be “druggable,” while AI and high throughput biology are connecting molecular design to cellular function. Yet the mission remains unchanged—using molecular approaches that leverage the cellular machinery to make progress against targets once deemed “undruggable.”
Continue reading “Targeted Protein Degradation: How Chemoproteomics and Induced Proximity Are Shaping Drug Discovery”Targeted protein degradation (TPD) is an emerging drug discovery strategy that offers an entirely different approach to tackle disease-relevant proteins, including classic “undruggable” targets. Instead of inhibiting protein function, small molecules like PROTACs and molecular glues co-opt the cell’s own ubiquitin-proteasome system to eliminate specific proteins altogether. But as this targeted approach gains traction, it also challenges existing methods for validating compound activity.
How do you confirm that degradation is happening in a biologically-relevant system? Can you validate protein degradation in real-time?
Continue reading “A New View of Protein Degradation with HiBiT and Live Cell Imaging”In targeted protein degradation (TPD), timing is everything. Understanding not just whether a degrader works—but how fast, how thoroughly and how sustainably—can dramatically influence early discovery decisions. Dr. Kristin Riching (Promega) dove into the real-time world of degradation kinetics in the webinar: Degradation in Motion: How Live-Cell Kinetics Drive Degrader Optimization, sharing how dynamic data provides a clearer view of degrader performance than traditional endpoint assays.
Whether you’re exploring your first PROTAC or optimizing a molecular glue series, the expertise offered in Dr. Riching’s presentation gives you actionable insights that will help you connect kinetic data to better therapeutic design.
For decades, the concept of “undruggable” targets has presented one of the most significant challenges in drug discovery. At our recent virtual event, Illuminating New Frontiers: Cracking the Undruggable Code, leading researchers and industry experts gathered to showcase cutting-edge technologies and fresh perspectives that are expanding the boundaries of therapeutic development. Over three engaging days, participants explored groundbreaking advances in targeting RAS signaling, leveraging protein degradation and induced proximity strategies, and exploring RNA as a therapeutic target.
The third annual Targeted Protein Degradation (TPD) Symposium just wrapped up last month. It was kicked off with Poncho Meisenheimer, VP of Research and Development at Promega, likening the gathering of researchers to “kids in a biology candy store.” This playful analogy captured the vibrant energy and sense of exploration among the attendees, who convened to delve into the future possibilities of proximity-induced degradation. Poncho left attendees with three key questions to consider throughout the symposium:
Nearly 150 participants from both industry and academia attended the two-day symposium. It was held on September 11th and 12th at Promega’s R&D hub, the Kornberg Center, in Madison, Wisconsin. The event, now in its third year, provided a familiar environment where collaborations flourished, and many attendees rekindled connections forged through previous interactions or partnerships in the field.
Continue reading “Third Annual Targeted Protein Degradation Symposium: Embracing the Excitement of Discovery”At the American Association for Cancer Research meeting in April 2016, then Vice President of the United States, Joe Biden, revealed the Cancer Moonshot℠ initiative— a program with the goals of accelerating scientific discovery in cancer research, fostering greater collaboration among researchers, and improving the sharing of data (1,2). The Cancer Moonshot is part of the 21st Century Cures Act, which earmarked $1.8 billion for cancer-related initiatives over 7 years. The National Cancer Institute (NCI) and the Cancer Moonshot program have supported over 70 programs and consortia, and more than 250 research projects. According to the NCI, the initiative from 2017 to 2021 resulted in over 2,000 publications, 49 clinical trials and more than 30 patent filings. Additionally, the launch of trials.cancer.gov has made information about all cancer research trials accessible to anyone who needs it (3).
“We will build a future where the word ‘cancer’ loses its power.”
First Lady, Dr. Jill Biden
In February 2022, the Biden White House announced a plan to “supercharge the Cancer Moonshot as an essential effort of the Biden-Harris administration” (4). Biden noted in his address that, in the 25 years following the Nixon administration’s enactment of the National Cancer Act in 1971, significant strides were made in understanding cancer. It is now recognized not as a single disease, but as a collection comprising over 200 distinct diseases. This period also saw the development of new therapies and enhancements in diagnosis. However, despite a reduction in the cancer death rate by more than 25% over the past 25 years, cancer continues to be the second leading cause of death in the United States [4].
The Cancer Moonshot is a holistic attempt to improve access to information, support and patient experiences, while fostering the development of new therapeutics and research approaches to studying cancer. In this article, we will focus on research, diagnostics and drug discovery developments.
Solving for Undruggable Targets
KRAS , a member of the RAS family, has long been described as “undruggable” in large part because it is a small protein with a smooth surface that does not present many places for small molecule drugs to bind. The KRAS protein acts like an off/on switch depending upon whether it has GDP or GTP bound. KRAS mutations are associated with many cancers including colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and pancreatic ductal adenocarcinoma (PDAC). The G12 position in the protein is the most commonly mutated; G12C accounts for 13% of the mutations at this site, and is the predominant substitution found in NSCLC, while G12D is prevalent in PDAC (5).
Continue reading “Cancer Moonshot: Solving Tough Problems”In the opening remarks of our second annual Targeted Protein Degradation Symposium, Tom Livelli, VP of Life Sciences Products & Services at Promega, posed a question to the attendees: “What do you want to be able to do today that you can’t?” This aspirational question set the tone for an event where building connections to advance the study and application of proximity-induced degradation took center stage.
More than 90 attendees from academia and industry gathered September 20–21 for the two-day symposium, which was hosted in our inspirational Kornberg Center—the R&D heart of Promega. Through engaging talks, a poster session, “Learn n’ Burn” challenges and social gatherings, participants had the opportunity to reinforce existing collaborations and to connect with others who are making an impact in the field of targeted protein degradation.
Traditional approaches for protein degrader compound screening like Western blotting can be laborious, time consuming and cannot be streamlined with automation. By implementing a high-throughput, automated workflow that uses our CRISPER/Cas9 knock-in cell lines, live-cell bioluminescent assays and sensitive GloMax® Discover microplate readers, our custom assay services offer protein degradation profiling at an accelerated rate.
To do this, we collaborated with HighRes® Biosolutions, to develop an automated system that can screen up to 100 384-well plates each day, generating roughly 40,000 data points with minimal hands-on work.
Learn how bioluminescent tools like HiBiT and NanoBRET™ technology can help you answer key questions in your targeted protein degradation research.
An important step of building this system is to integrate four GloMax® Discover microplate readers into the automated system using instrument’s built-in SiLA2 communication driver. The driver software makes it easy to connect the microplate readers with HighRes® Biosolution’s robotic components.
Check out our setup in the video below.
