CETSA ®: Accelerating Drug Discovery from Bench to Bedside with Michael Dabrowski, Pelago Bioscience AB

About the Interviewee

Michael Dabrowski is the Chief Executive Officer (CEO) and one of the Co-Founders of Pelago Bioscience AB.

Michael Dabrowski is a seasoned scientist and executive with a robust academic background and extensive experience in biophysics, electrophysiology, and ion channel pharmacology. He earned his Master of Science in Biophysics from the University of Copenhagen, followed by a Doctor of Philosophy in Electrophysiology from Aarhus University. During his graduate studies, he developed expertise in macropatch recording techniques, focusing on the functional and molecular characterization of ATP-sensitive potassium ion channels, and trained several students in these methods.

After completing his Ph.D., Dr. Dabrowski conducted post-doctoral research at Oxford University, where he studied the structure, function, and in vitro pharmacology of ATP-sensitive potassium channels involved in glucose sensing and insulin secretion in pancreatic beta-cells. His work at Oxford, where he also served as a Robert Turner Visiting Scholar at Green College, solidified his reputation in the field of ion channel research.

Dr. Dabrowski’s professional career at AstraZeneca spanned over a decade, where he held various roles, including Senior Research Scientist, Associate Principal Scientist, and Head of the Ion Channel Initiative. In these positions, he led research initiatives and developed the early Neurology Portfolio within AstraZeneca’s CNSP iMed, driving projects from concept to lead generation in alignment with the company’s disease area strategy.

In 2013, Dr. Dabrowski co-founded Pelago Bioscience AB in Stockholm, Sweden, with the vision to advance drug discovery through the application of the CEllular Thermal Shift Assay (CETSA®) technology platform. Since then, he has served as the company’s CEO, overseeing the development and commercialization of CETSA® to enable target engagement studies, which are critical in early drug discovery. His leadership at Pelago has been instrumental in establishing the company as a key player in the biotechnology field.

The Discussion

Driving Forces Behind a Career in Drug Discovery and Leadership at Pelago

[Dex Marco]: It’s such a pleasure to have you here with us today, Dr. Dabrowski. So, Michael, with more than 25 years of Drug Discovery experience in diabetes, pain, and neurology, and a proven track delivery record of science, project, people, and budget management, what would you say drove you towards this field, and what brought you to eventually Co-Found and become the CEO of Pelago Bioscience AB?

[Michael]: I am a scientist by training, but I quickly realized that while I am deeply interested in science and technology, my true passion lies in their practical applications—the problems they solve and the value they generate. My focus has always been on using science to address real-world challenges This has been the driving force throughout my career.

After my postdoctoral work, I joined AstraZeneca in Sweden, continuing my mission of finding drugs to cure diseases or, at the very least, alleviate symptoms. My transition to co-founding Pelago Bioscience and becoming its CEO was a natural progression. The CETSA technology, invented at Karolinska Institute in Stockholm, is a fantastic innovation grounded in solid basic science. The technology addresses the critical problem of determining whether a drug reaches its intended target and quantifying target engagement. Moving from Big Pharma to the service sector with Pelago was not a difficult leap because the purpose remains the same—enabling others to discover new drugs.

[Dex Marco]: It’s inspiring to hear how your passion for applying science to solve real-world problems led you to co-found Pelago Bioscience, Michael.

The Evolution and Unique Features of CETSA®: Positioning Pelago as a Leader

[Dex Marco]: Pelago Bioscience AB is founded to accelerate the use and value of cellular thermal shift assay in drug discovery and diagnostics. Can you elaborate on the development and unique features of the CETSA® technology platform, and how it has positioned Pelago as a leader in early drug discovery?

[Michael]: The CETSA® method was invented based on solid basic science, particularly the understanding of proteins, protein structure, and thermodynamics. However, it was also developed with a keen eye on its practical applications. When the inventors of the CETSA® technology first sent me the manuscript, which was eventually published in Science, I could literally go through each figure and think, ‘If I had known this in figure one four years ago, I would have made different decisions in that particular project at AstraZeneca.’ In figure two, I realized that, had we known this, we could have enabled two more projects to move forward. From the very start, there was a strong focus on the utility of the method, which had already been proven in that Science paper published in the summer of 2013. Pelago was founded a few months later, in late 2013.The CETSA method was invented based on solid basic science, particularly the understanding of proteins, protein structure, and thermodynamics. However, it was also developed with a keen eye on its practical applications. When the inventors of the CETSA technology first sent me the manuscript, which was eventually published in Science, I could literally go through each figure and think, ‘If I had known this in figure one four years ago, I would have made different decisions in that particular project at AstraZeneca.’ I realized that, had we known this, we could have enabled more projects to move forward. From the very start, there was a strong focus on the utility of the method, which had already been proven in that Science paper published in the summer of 2013.

In those early months and years, we engaged in discussions with drug discoverers about how they would apply this technology and what kinds of problems it could solve. Their feedback was invaluable in helping us continue to develop the method and expand its applications to enable drug discovery with increased success rates.

The method itself is remarkably simple, consisting of four steps: treat, heat, separate, and detect the protein, with the purpose of quantifying physiological relevant target engagement. Because target engagement is a prerequisite for a drug having its intended effect. Knowing this early in the drug discovery process is incredibly valuable. While CETSA is not the first method to quantify target engagement, it may be the most versatile and the development of Pelago over the last 10 years proves its value.

Two key features make the CETSA method particularly powerful. First, it can be used in any sample matrix—whether your biology takes place in cells or tissue, that’s where we measure target engagement. Second, it requires no tags or labels, meaning you don’t alter the drug you’re exploring, the target, or the biology. This means that it is physiologically relevant.

The method is quite simple, but the devil is in the details. As the owner of the patent, we’ve optimized the workflow to be highly effective in generating this type of data.

[Dex Marco]: Thank you for that comprehensive overview, Dr. Dabrowski. It’s clear that CETSA® not only fills a critical gap in drug discovery but also does so with a level of precision and versatility that truly sets it apart. The focus on real-world application from the outset is particularly impressive.

Comparing CETSA® with Traditional Methods: Advancements in Measuring Target Engagement

[Dex Marco]: Pelago Bioscience leverages the chemoproteomics method enabling measurements of compound target engagement in intact cells and tissue, without modifications to the target protein. How does Pelago’s approach to measuring target engagement differ from traditional methods, and what advantages does it offer in understanding the biological effects of potential drug candidates?

[Michael]: In traditional methods, detection of target engagement typically focuses on one protein species at a time. Pelago Bioscience’s approach can expand beyond this. Instead of asking which compounds interact with a single target, you can reverse the problem and ask how a few specific compounds interact with all the proteins in the cell. This approach, also using mass spectrometry, is particularly effective in addressing molecular Mode of Action and challenges of specificity and selectivity.

Moreover, our method allows us to explore the downstream consequences of drug binding. When a drug binds to a protein, it triggers a cascade of biochemical reactions—such as modifications, translocations, aggregation, or disaggregation of proteins—that we can detect in an unbiased proteomics format. This capability is valuable not only for understanding selectivity and specificity but also for pathway analysis and deconvoluting the effects of phenotypic drug discovery.

[Dex Marco]: It’s truly fascinating to see how Pelago’s approach not only enhances specificity and selectivity but also provides a deeper understanding of the broader biological impact of potential drug candidates.

Key Collaborations and the Extended Team Approach: Benefits and Impact on Drug Discovery

[Dex Marco]: Pelago prides itself on being the partner of choice for many drug discovery projects. AstraZeneca, where you developed and managed the early Neurology Portfolio, applies Pelago’s CETSA in hit identification and lead optimization and Grey Wolf Therapeutics considers CETSA data as a keystone in their structure-activity relationship or SAR analysis. In line with this, can you discuss these key collaborations and more, and how Pelago’s extended team approach benefits these partnerships?

[Michael]: As a growing organization, our goal is to make this technology available for maximum use and value in drug discovery and diagnostics. We don’t want to be a bottleneck. This is why we take on various roles, as both service partner and consulting partner and sometimes even license provider for large pharma, midsize pharma, biotech companies and virtual organizations.

Ultimately, we strive to be seen as the ‘guys down the hall’—whether we’re bringing the pipettes or adding brainpower to the projects, we’re our customer’s extended team.

[Dex Marco]: It’s impressive to see how Pelago adapts to the needs of different partners—acting as the biology lab for virtual companies while providing expert consulting for larger organizations. The flexibility in tailoring partnerships to the specific dynamics and portfolios of each company truly highlights the versatility and impact of CETSA®.

Enhancing Speed and Reliability in Drug Discovery: The Role of CETSA® Technology

[Dex Marco]: In the competitive landscape of drug discovery, timing and accuracy can make or break a project. Speed and certainty are no doubt critical in drug development. How does Pelago’s technology and expertise enable faster and more reliable target engagement data, and what impact does this have on the overall drug discovery timeline? What specific aspects of the CETSA® platform contribute to this increased speed and reliability?

[Michael]: At Pelago, our mission is toensure that all projects know their targets before entering clinical development. For that purpose, we tailor our effort to the specific needs of each client. For virtual companies with just one asset, speed is essential for a rapid path to the clinic. In contrast, larger companies with extensive portfolios might focus on balancing and mitigating risks across their various projects, allowing for more flexibility in timelines for individual projects.

The concept of ‘time-critical’ can vary depending on the client’s situation. For some, speed is the top priority, while for others, certainty and accuracy are more crucial. CETSA excels in providing all three. It can be used to obtain early, reliable target engagement data, which is vital for making informed decisions about advancing projects.

The versatility of CETSA allows us to adapt our approach to each company’s specific needs and goals. This flexibility is reflected in our various types of partnerships. For large pharmaceutical companies, like AstraZeneca, we offer consulting and guidance on how best to apply the technology. For biotech companies and virtual organizations, we act as the biology lab, providing the CETSA data and, in some cases, downstream functional assays to correlate target engagement with biological outcomes.

Our founding team, Professor Pär Nordlund the inventor of CETSA, Daniel Martinez Molina who operationalized the technology and myself, has always had a strong customer focus. From the beginning, we engaged directly with clients to understand their specific challenges and needs. This approach allowed us to tailor our solutions to address their problems effectively, ensuring that our technology not only delivers valuable data quickly but also aligns with the strategic goals of each drug discovery project.

[Dex Marco]: In any industry, especially within drug discovery, the ultimate goal is to deliver value by being customer-centric and client-oriented, which is precisely how Pelago operates.

Ensuring Target Clarity in Drug Discovery: Pelago’s Approach and Its Importance

[Dex Marco]: Pelago’s mission emphasizes the importance of target clarity in drug discovery. How does Pelago ensure that drug discovery projects have a clear understanding of their targets before clinical trials, and why is this clarity crucial for the success of novel therapeutics?

[Michael]: I am a drug discoverer by training and have led many projects, always with the belief that a project will advance all the way to the pharmacy and ultimately help treat patients. However, achieving this is extremely rare in early discovery.

So, how do we ensure success? It might sound bold, but we aim to be the partner of choice in discovering novel therapeutics. The underlying premise is that if we achieve physiological relevance in target engagement quantification and correlate that to relevant functional outcomes this will increase the likelihood of successfully developing a therapeutic. We therefore focus on understanding how much target engagement leads to a therapeutic effect. Ultimately, this approach allows us to ensure that all projects have a thorough understanding of their targets before advancing to clinical stages.

[Dex Marco]: I’m genuinely impressed by how the Cellular Thermal Shift Assay (CETSA) evolves beyond its seemingly simple name to become a powerful drug discovery tool. What stands out is how you’re scaling physiological effects from a cellular level to tissue and organ-system levels, and eventually to broader scales. By integrating various omics approaches and assessing potential impacts on different pathways, your technology offers a comprehensive understanding before a drug reaches the market. This proactive approach helps prevent issues that have led to drug recalls in the past, making CETSA a truly promising tool for your clients.

[Michael]: Absolutely, that’s our goal. While we’re not a safety or toxicology lab, CETSA provides crucial insights by identifying potential issues early on, with its built-in translational power. This technology can flag concerns that suggest further exploration is needed, helping clients address these issues before proceeding to clinical trials.

We’ve discussed quantifying target engagement and correlating it with relevant functional readouts. The next step for us is to introduce a third dimension: determining whether the effect is beneficial or detrimental. In different therapeutic areas, the same effect can be interpreted differently. For example, in an analgesic project, such as developing a new headache pill, the goal is to ensure minimal toxicity, as the medication should be safe for daily use with few side effects. In contrast, for oncology, where the objective is to kill cancer cells, specific cell toxicity is desired.

[Dex Marco]: I’m intrigued by this third dimension you’ve introduced. It brings to mind a quote from Paracelsus: “The difference between a drug and a poison is in the dose.” What might be beneficial in treating cancer could indeed be detrimental when applied to something as benign as a headache.

Future Vision for Pelago: Essential Qualities and Skills for Continued Success and Growth

[Dex Marco]: Mike, given your extensive experience and expertise at the intersection of science and technology, how do you envision your future roles as the CEO of Pelago Biosciences AB, the Home of CETSA®? What key qualities or skills do you believe will be most essential to drive the company’s success and maintain its position as a leading provider of customized services, from confirming target engagement to strengthening target validation and understanding the mechanism of action of compounds, to help clients make better decisions faster, no matter where they are in the drug discovery process?

[Michael]: As I look to the future, I see Pelago Bioscience evolving in alignment with the technology diffusion curve. Initially, we engaged the tech enthusiasts and visionaries, but now we are moving into the broader market. We have demonstrated that our technology works, and that we are the leading expert in cellular target engagement, and our goal is to extend our reach to every project before it enters clinical trials.

To achieve this, we must evolve from merely removing roadblocks to becoming a key partner that stays engaged throughout the project lifecycle. This involves expanding our technology and capacity to offer a more comprehensive service package. By doing so, we aim to become the preferred partner for both virtual companies and larger biotech firms, who may delegate entire projects to us.

While we do not intend to be a fully integrated service provider from A to Z, we are committed to growing our capabilities. This will enable us to support projects more effectively and engage with the numerous opportunities in the drug discovery pipeline. As we grow, our enhanced capabilities and stronger voice will allow us to impact a larger number of projects, ultimately driving greater success for our clients and the industry as a whole.

[Dex Marco]: Wow, it’s impressive to hear about Pelago’s focus on expanding technology and capacity to serve as a practical extended team for virtual companies. The addition of the third dimension you mentioned is particularly exciting, as it will strengthen Pelago’s position and enable us to handle multiple projects simultaneously. This growth will enhance Pelago’s voice and broaden our impact, allowing us to collaborate with various companies and manage numerous projects in parallel using our technology.

[Michael]: While CETSA is at the core of what we do at Pelago, the ultimate goal extends beyond the technology itself. As we progress, our focus shifts from the technology to addressing the needs of our clients—the problem owners.

As we continue to evolve and aim to solve a broader range of challenges for our clients, the emphasis on technology will naturally diminish. What becomes paramount is the value we deliver through our partnerships and the tangible improvements in human health.

So yes, expanding our capacity and incorporating additional technologies are essential, but our true mission is to improve human health. Ultimately, it’s about enabling the discovery of novel therapies that make a real difference in patients’ lives. This focus on meaningful outcomes and effective problem-solving defines the future of Pelago Bioscience.

[Dex Marco]: I appreciate your humility, especially given the power and impact of CETSA® as a tool. It’s refreshing to see someone at the forefront of the industry recognize their role within the broader drug discovery landscape. Your perspective on the importance of collaboration and problem-solving, beyond just the technology itself, is truly commendable.

[Michael]: Thank you for your kind words. I thoroughly enjoyed our discussion and appreciate your insightful interpretations of my points. It’s impressive how you expanded on the brief bullet points we provided. Thank you very much for your thoughtful engagement.

Engr. Dex Marco Tiu Guibelondo, B.Sc. Pharm, R.Ph., B.Sc. CpE

Editor-in-Chief, PharmaFEATURES

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