Small-Molecule Drug Discovery

Cracking the Undruggable Code: Top 10 Key Takeaways

Posted on by Sara Christenson

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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Targeting Dark Kinases for Non-Hormonal, Reversible Male Contraceptives

Posted on by Anna Bennett

Contraception, or birth control, is an important tool in family planning. Given the fourfold increase in population over the last century1 there is a clear need for more affordable, reversible, and safe methods of contraception. At present, the responsibility of taking contraceptives falls largely on people with female reproductive organs as there is no current method of birth control for people with male reproductive organs. The search for a non-hormonal, male birth control has been an elusive goal in the field of reproductive health.

A complex, futuristic scene within the outline of a pill.

Recently, a group of scientists from Baylor College of Medicine with contributions from Promega scientists identified a novel compound that 1) inhibits a specific kinase and 2) functions as a reversible male contraceptive. The kinase targeted in this study is the serine/threonine kinase 33 (STK33); a genetic knockout of this gene in male mice is known to cause sterility. The team published their work in Science and utilized a suite of approaches—including DNA-Encoded Libraries (DELs), crystallography, and cellular NanoBRET™ Target Engagement Kinase Assays—to discover a potent inhibitor of STK33 (CDD-2807).  The CDD-2807 inhibitor has shown promising results in inducing reversible contraception in male mice, marking a significant milestone in the development of non-hormonal contraceptive options. Let’s dive into the foundation, novel methodology, collaboration, and implications for this work.

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

Posted on by Anna Bennett

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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Cancer Moonshot: Solving Tough Problems

Posted on by Michele Arduengo

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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Can AI Replace High-Throughput Screens for Drug Discovery?

Posted on by Johanna Lee
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

Posted on by Kendra Hanslik

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

Posted on by Jordan Nutting

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?

Posted on by Ken Doyle

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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Cell-Based Target Engagement and Functional Assays for NLRP3 Inhibitor Profiling Help Identify Successes and Failures

Posted on by Kari Kenefick

Identifying Inflammasome Inhibitors: What’s Missing
The NLRP3 inflammasome is implicated in a wide range of diseases. The ability to inhibit this protein complex could provide more precise, targeted relief to inflammatory disease sufferers than current broad-spectrum anti-inflammatory compounds, potentially without side effects.

Studies of NLRP3 inflammasome inhibitors have relied on cell-free assays using purified NLRP3. But cell-free assays cannot assess physical engagement of the inhibitor and target in the cellular micro-environment. Cell-free assays cannot show if an NLRP3 inhibitor enters the cell, binds the target and how long the inhibitor binding lasts.

Cell-based assays that interrogate the physical interaction of the NLRP3 target and inhibitor inside cells are needed.

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Promega qPCR Grant Series #3: Immunotherapy Researcher, Dr. Sabrina Alves dos Reis 

Posted on by Anna Bennett
Professional headshot image of Dr. Sabrina Alves dos Reis, subject of the blog post
Sabrina Alves dos Reis

In our third and final installment of the Promega qPCR Grant Recipient blog series, we highlight Dr. Sabrina Alves dos Reis, a trained immunotherapy researcher. Her work has focused on developing tools for more accessible cancer therapies using CAR-T cells. Here, we explore Dr. Alves dos Reis’ academic and scientific journeys, highlight influential mentorship and foreshadow her plans for the Promega qPCR grant funds. 

Dr. Alves dos Reis’ career began with a strong affinity for biology. As an undergraduate student, she pursued a degree in biological science, where she developed a foundational understanding for designing and developing research projects. As her passion for science heightened, she decided to continue her journey in science, culminating in a PhD at the Fundação Oswaldo Cruz Institute in Rio de Janeiro, Brazil. Her research projects focused on the unexplored territory of adipose tissue as a site for Mycobacterium leprae—or leprosy bacillus—infection. She mentioned that this work piqued her curiosity for improving immunotherapies and laid the foundation for her future in cancer research.  

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