Biologic Drug Discovery

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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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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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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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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Macrophages: The Unsung Heroes of Immune Response and Biologic Drug Development 

Posted on by Johanna Lee

When we think about the immune system, B cells and T cells are often the focus of attention. B cells are known for producing antibodies, and T cells are celebrated for their cytotoxic capabilities. More recently, however, macrophages are being brought into the spotlight and recognized for their integral role in immune defense and the field of biologic drug development. 

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Uniting Diverse Minds, Vibrant Ideas, and Collaborative Spirit at the 2023 Biologics Symposium

Posted on by Shannon Sindermann
Biologics Symposium

On Thursday November 9th, 2023, Promega held its 7th Biologics Symposium at the Babraham Research Campus in Cambridge. For the first time, participants had the option to attend the event either in person or experience it via live stream, creating an inclusive and dynamic environment where the latest breakthroughs and ideas could be showcased. Moreover, the event was organized into a morning and afternoon session, enabling ample time for networking and the exchange of ideas beyond formal presentations.

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Cancer Preventing Vaccines: Unleashing the Potential of Tumor Antigens

Posted on by Sara Christenson

It has been more than 100 years since Dr. William B. Coley, known today as the “Father of Immunotherapy,” made the first recorded attempt to mobilize the immune system as a means of treating cancer (9). Decades later, the discovery of T cells and the vital role they play in the immune system set the groundwork for many new immunotherapy treatments, such as those involving monoclonal antibodies, cytokines, CAR T cells, and checkpoint inhibitors.

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

Posted on by Ken Doyle

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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Monoclonal Antibody (mAb) Therapy to Delay the Onset of Type 1 Diabetes

Posted on by Ken Doyle

On November 18, 2022, the US Food and Drug Administration (FDA) announced the approval of the first drug to delay the onset of stage 3 type 1 diabetes (T1D). The monoclonal antibody (mAb) drug, teplizumab, was approved for use in adults and pediatric patients 8 years and older.

3D illustration of a monoclonal antibody

The road to approval has been a bumpy one for the manufacturer, Provention Bio. In 2020, the FDA rejected the application for teplizumab due to several concerns, including the small size of the clinical trial. With the current approval, based on new clinical trial results, Provention Bio confirmed a co-promotion agreement with Sanofi US. The agreement included a $35 million Sanofi equity investment in the company.

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Small Molecule Therapies and Immunotherapies: An Introduction to Targeted Cancer Treatments

Posted on by Kelly Grooms

Cancer is a deceptively singular term for hundreds of different diseases. These diseases can affect almost any part of the body.  In the United States, cancer is the second most common cause of death (1). At its most basic level, however, cancer is the abnormal and uncontrolled division of cells resulting from genetic changes in one or more cells.

This prolific cell division is what many standard chemotherapies act upon. These therapies are developed to kill rapidly dividing cells but often don’t discriminate between normal and cancerous cells. In contrast, targeted therapies are designed to interact with (or target) specific pathways, processes or proteins whose abnormal behavior is associated with cancer development and growth. Targeting these abnormal cellular functions can counteract cancer in different ways. They can interfere with tumor growth, carry other drugs into tumor cells or help the immune system find and kill cancerous cells. Targeted therapies can be loosely divided into two categories: small molecule therapies and immunotherapies.

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