Targeted Protein Degradation (PROTACs)

Targeted Protein Degradation: How Chemoproteomics and Induced Proximity Are Shaping Drug Discovery

Posted on by Amy Landreman

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.” 

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A New View of Protein Degradation with HiBiT and Live Cell Imaging

Posted on by Anna Bennett

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?  

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Unlocking the Power of Live-Cell Kinetics in Degrader Development

Posted on by Kelly Grooms

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.

3D visualization of a protein structure within a live-cell environment, highlighting the interaction site relevant to targeted protein degradation, set against a dark cellular background to emphasize kinetic dynamics.
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Cracking the Undruggable Code: Top 10 Key Takeaways

Posted on by Sara Millevolte

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.

Target engagement of RAF dimer inhibitor LXH254 at RAF kinases, in complex with KRAS (blue). RAF inhibitor LXH254 engages BRAF or CRAF protomers (orange), but spares ARAF (red). Unoccupied ARAF is competent trigger downstream mitogenic signaling (lightning bolts). Red cells in the background are fluorescently labeled RAS proteins, expressed in live cells.
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Third Annual Targeted Protein Degradation Symposium: Embracing the Excitement of Discovery

Posted on by Simon Moe

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:

  1. How can we focus on quantitative measures of cellular events in relevant models?
  2. How do we generate results that serve both human and AI models?
  3. How do we best embrace the excitement of discovery?

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.

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Cancer Moonshot: Solving Tough Problems

Posted on by Michele Arduengo, PhD

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).

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Insights from our Second Annual Targeted Protein Degradation Symposium

Posted on by Jordan Nutting

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.

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Scaling Up to Measure 40,000 Data Points a Day with GloMax® Microplate Readers

Posted on by Jordan Nutting

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.

See how we’ve integrated GloMax® Discover microplate readers into a high-throughput automated system for profiling protein degraders in live cells.
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Inside the First Promega Targeted Protein Degradation Symposium

Posted on by Jordan Villanueva
Poster session at the Targeted Protein Degradation Symposium
Researchers attend a poster session at the first Targeted Protein Degradation Symposium

On September 20, more than 60 scientists from across North America convened at Promega Madison for our first Targeted Protein Degradation Symposium. For two days, speakers shared their most recent advances in this exciting field.

“What has really stood out for me is the collective energy, the openness, the willingness of people to share their struggles, their successes, their compound structures, and really embody this broader goal of working together to build capabilities that will ultimately lead to successful therapeutic compounds,” says Promega Senior Research Scientist Kristin Riching.

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PROTACs: Just the FAQs

Posted on by Ken Doyle
protac drug discovery

While PROTACs might not be the topic of conversation at high society cocktail parties, or merit cover stories in glamor magazines, they’re certainly shaking up the drug discovery industry. PROTAC® degraders, together with related compounds like molecular glues and LYTACs, are the basic tools for a targeted protein degradation strategy. Research in this field is advancing rapidly, enabling the development of therapies for disease targets disease targets previously thought to be “undruggable”. This blog post provides an overview of PROTACs based on frequently asked questions.

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