From Tracers to Kinetic Selectivity: Highlights from the Target Engagement in Chemical Biology Symposium

In April 2024, Promega hosted the “Target Engagement in Chemical Biology Symposium” at the Kornberg Center, a research and development hub on Promega’s campus in Madison, Wisconsin. The goal of the symposium was to gather interdisciplinary researchers interested in the field of small molecule target engagement to foster collaboration through knowledge sharing and innovation. The symposium featured a 1.5-day agenda packed with 23 speakers, 4 workshops, poster sessions and social events. Over 130 attendees gathered to participate in the multifaceted event, with participants from different geographic regions and in different research sectors from academia to government to industry.  

People gather in a large atrium with scientific posters and table displays.
Attendees gather for the poster session in Kornberg Atrium. Photo by Anna Bennett (Promega Corporation)

The symposium highlighted the collective commitment to overcoming the challenges in drug discovery by developing more targeted and efficacious treatments, driven by a shared determination to create innovative solutions that address unmet medical needs. While we cannot share all the exciting research presented at the symposium, we are thrilled to highlight a few talks that exemplify the novel work and collaborative spirit of this research community.  

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Can AI Replace High-Throughput Screens for Drug Discovery?

This image was created with the assistance of AI

For decades, pharmaceutical companies have relied on high-throughput screening (HTS) as the first step in the drug discovery process. After an initial screening of thousands of compounds, scientists select a smaller list of candidate drugs that is then used for further downstream testing. A major limitation to HTS, however, is the need to synthesize all compounds used in the screen—the compounds need to physically exist to be tested. This significantly limits the number of compounds that can be tested, hindering the discovery of new drugs.

What if we could test compounds even before they are synthesized?

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Decades of Discovery: How the NCI-60 Revolutionized Cancer Drug Screening

The National Cancer Institute’s NCI-60 drug screening panel, comprised of 60 diverse human cancer cell lines, has been a cornerstone in advancing cancer research and drug discovery since its inception in the late 1980s. Developed in response to the need for more predictive and comprehensive preclinical models, the NCI-60 facilitates the screening of thousands of compounds annually, aiming to identify potential anti-cancer drugs across a broad spectrum of human cancers. This article traces the origins, development, and evolution of the NCI-60 panel, highlighting its significant role in advancing our understanding of cancer and therapeutic agents.  

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Discovering Cyclic Peptides with a “One-Pot” Synthesis and Screening Method

In the evolving landscape of drug discovery, cyclic peptides represent an exciting opportunity. These compounds offer a unique balance of size and specificity that positions them to bridge the gap between small molecule drugs and larger biologics like antibodies.

However, most cyclic peptides demonstrate low oral bioavailability: they are digested in the stomach before they can enter the bloodstream, or they’re not absorbed into the bloodstream by the gastrointestinal tract and can have little therapeutic effect (1). Biologics face a similar challenge and are administered intravenously rather than with a more convenient pill form.

A 384 well plate next to a collection of pills of different sizes and shapes.


To address the challenge of low oral bioavailability of cyclic peptides, a team from the Ecole Polytechnique Fédérale de Lausanne in Switzerland developed a “one-pot” method to synthesize a diverse library of cyclic peptides, which they then screened for stability, activity and permeability (1). Their method, which was published December 2023 in Nature Chemical Biology, streamlined the process of identifying and optimizing cyclic peptides and marked a substantial improvement from their earlier studies, where the developed cyclic peptides exhibited almost no oral bioavailability (%F). Using this new method, the team successfully developed a cyclic peptide with 18%F oral bioavailability in rats.

This blog covers the details of this study as well as a brief background on cyclic peptides.

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Will Artificial Intelligence (AI) Transform the Future of Life Science Research?

Artificial intelligence (AI) is not a new technological development. The idea of intelligent machines has been popular for several centuries. The term “artificial intelligence” was coined by John McCarthy for a workshop at Dartmouth College in 1955 (1), and this workshop is considered the birthplace of AI research. Modern AI owes much of its existence to an earlier paper by Alan Turing (2), in which he proposed the famous Turing Test to determine whether a machine could exhibit intelligent behavior equivalent to—or indistinguishable from—that of a human.

The explosive growth in all things AI over the past few years has evoked strong reactions from the general public. At one end of the spectrum, some people fear AI and refuse to use it—even though they may have unwittingly been using a form of AI in their work for years. At the other extreme, advocates embrace all aspects of AI, regardless of potential ethical implications. Finding a middle ground is not always easy, but it’s the best path forward to take advantage of the improvements in efficiency that AI can bring, while still being cautious about widespread adoption. It’s worth noting that AI is a broad, general term that covers a wide range of technologies (see sidebar).

AI personified looking at a dna double helix against an abstract cosmic background
Image generated with Adobe Firefly v.2.

For life science researchers, AI has the potential to address many common challenges; a previous post on this blog discussed how AI can help develop a research proposal. AI can help with everyday tasks like literature searches, lab notebook management, and data analysis. It is already making strides on a larger scale in applications for lab automation, drug discovery and personalized medicine (reviewed in 3–5). Significant medical breakthroughs have resulted from AI-powered research, such as the discovery of novel antibiotic classes (6) and assessment of atherosclerotic plaques (7). A few examples of AI-driven tools and platforms covering various aspects of life science research are listed here.

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Insights from our Second Annual Targeted Protein Degradation Symposium

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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Genome-Wide CRISPR Screening: Putting Death on Hold

We share this planet with approximately 8.7 million species of plants and animals. Within such a diverse environment, it’s only natural that many complex relationships have developed among different species. Some relationships are mutually beneficial, some are parasitic—and some are lethal.

Genome wide - crisper screening to help with toxic compounds to humans

Natural toxins and venoms are biologically active compounds produced by normal metabolic processes in an organism but are harmful to other organisms. Typically, toxins are encountered passively or ingested by the affected organisms, and have a specific mode of action and binding site within a cell. In contrast, venoms are introduced directly into the victim through a specialized delivery mechanism, and they may consist of a mixture of compounds that affect a range of cell types and tissues (1). Both types of poisons are produced for predation, defense, or to offer a competitive advantage (1).

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PARP and DDR Pathways: Targeting the DNA Damage Response for Cancer Treatment

Our cells, and the DNA they contain, are under constant attack from external factors such as ionizing radiation, ultraviolet light and environmental toxins. Internal cellular processes can also generate metabolites, such as reactive oxygen species, that damage DNA. In most cases, DNA damage results in permanent changes to DNA molecules, including DNA mismatches, single-strand breaks (SSBs), double-strand breaks (DSBs), crosslinking, or chemical alteration of bases or sugars. If left unchecked, DNA damage can cause genome instability, mutations and aberrant transcription, and oncogenic transformation.

PARP DDR pathway for drug discovery

Fortunately, our cells have also evolved multiple pathways to repair damaged DNA, collectively known as the DNA damage response (DDR). The type of repair mechanism depends on the nature of the damage, and whether the damage occurs in mitochondrial or nuclear DNA. These mechanisms have been reviewed extensively (1,2). Recently, considerable attention has focused on pathways for repairing SSBs and DSBs, mediated by the ADP-ribosylating enzyme known as poly (ADP-ribose) polymerase 1, or PARP-1.

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MISpheroID: A Knowledgebase to Improve Reproducibility in Spheroid Research

Spheroid research is  now a common component of cell biology and drug discovery science

Advantages of Spheroids

In the past decade, there has been a sharp rise in studies using spheroids as cell models for basic research and drug discovery. Spheroids are self-organized aggregation of cells that form a spherical mass, and they have become widely popular because they are much more physiologically relevant compared to flat 2D cell cultures.

In spheroids, the inner cells have less access to nutrients and oxygen compared to the outer layer, forming a natural gradient. As a result, metabolite concentration and cellular state such as proliferation and differentiation, can be very different at the periphery compared to the inner core. This phenomenon, known as “heterogeneity”, makes 3D tumor spheroids much more representative of actual tumors in the human body.

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Save Precious Time with Same-Well Multiplexing

Scientist performing a multi-well assay. Same-well multiplexing enables you to look at one event from several perspectives.

A graduate student believes he has mastered the art of “the assay”. No need to run duplicates, he knows exactly which one will get him the answers he needs right away.  

To challenge this, his PI proposes an exercise. He asks of the graduate student, “What happens when you treat cells with doxorubicin?”

The graduate student raises his cells, treats them accordingly, and decides to run a cell viability assay to determine their fate. He returns to the PI with the final verdict: his cells are dead.

The PI takes a look at the data and asks the graduate student to repeat the experiment with an additional assay for cytotoxicity―but the cytotoxicity assay shows that the cell membranes are intact, which only puzzles the graduate student. The PI asks him to run a third assay for apoptosis, and when the student does so, it becomes clear that the cells are dying.

The PI uses this opportunity to make his point: “Now do you see why I ask for more than one assay?”

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