Lyn Jones, PhD
Faculty Member, Principal Investigator, Chemical Biology Program and Department of Pediatric Oncology, Dana-Farber
In recent years, scientists have identified many of the proteins that help cancers grow, survive, and resist treatment. Some have become the basis for highly effective targeted therapies, but many others remain beyond the reach of existing medicines. Lyn Jones, PhD, Principal Investigator and Faculty Member of the Department of Pediatric Oncology and Chemical Biology Program at Dana-Farber Cancer Institute, is developing innovative drug discovery technologies designed to help researchers reach these elusive cancer-driving proteins and create new treatment opportunities for patients.
Jones arrived at Dana-Farber in 2019 after more than two decades in the pharmaceutical and biotechnology industries, where he led drug discovery efforts against some of the field’s most challenging targets. Now with his team at Dana-Farber, he is applying that experience to develop new chemistries that could dramatically expand the number of proteins scientists can target with medicines.
“Many of the most compelling therapeutic targets in cancer are also the most difficult to drug,” Jones says. “Our goal is to develop the chemistry needed to address those challenging targets.”
Expanding the Covalent Drug Discovery Toolkit
Jones’s laboratory specializes in covalent drugs—medicines that permanently attach to a target protein to modulate or block its activity. Unlike conventional drugs, which bind temporarily and then dissociate, covalent drugs remain attached to their targets, often producing stronger and more durable effects.
Several widely used cancer therapies, including ibrutinib for blood cancers, osimertinib and afatinib for lung cancer, and the KRAS-targeted drug sotorasib, rely on covalent binding to achieve durable inhibition of cancer-driving proteins.
Historically, however, most covalent drug discovery has focused on targeting a single amino acid called cysteine, but this is not ideal.
“Cysteine is relatively rare, and resistance can emerge if cancers mutate the cysteine that’s being targeted,” Jones says.
To overcome those limitations, Jones and his colleagues are developing new chemistries capable of targeting other amino acids, including lysine, tyrosine, and histidine. Because these amino acids are far more common across proteins, they offer a much larger landscape for drug discovery.
The ability to selectively engage these alternative amino acids could dramatically expand the number of proteins that scientists can target therapeutically, creating new opportunities to address cancers that have resisted conventional treatment approaches.
Expanding What’s Possible in Drug Discovery
These new chemistries are already opening doors to discoveries that were not possible even a few years ago. For instance, in a Chemical Science review published in 2025, Jones outlined how a new class of chemical reactions—called sulfonyl exchange chemistry—can help drugs attach to amino acids beyond cysteine. Because these amino acids are far more common across proteins, this chemistry dramatically expands the number of proteins scientists can realistically pursue as drug targets.
Finding New Opportunities for Drug Discovery
Developing new chemistry is only part of the challenge. Researchers must also identify where and how that chemistry can be applied to cancer-driving proteins.
We can now begin thinking about ways to target proteins that have historically been considered undruggable.
Lyn Jones, PhD
To do that, Jones’s laboratory combines synthetic chemistry, structure-guided drug design, and chemoproteomics, a technology that allows researchers to study how chemical probes interact with thousands of proteins inside living cells.
Together, these approaches help the team uncover previously hidden opportunities for therapeutic intervention. Among the most intriguing are so-called cryptic binding sites—protein pockets that appear only under certain conditions but can provide entirely new opportunities for drug design.
Jones explains that for him, the broader goal is not simply to create better drugs, but to expand the range of cancer-related proteins that researchers can realistically pursue as therapeutic targets.
“We can now begin thinking about ways to target proteins that have historically been considered undruggable,” he says.
By combining new chemistry with powerful tools for studying proteins, Jones and his colleagues are helping reveal biological vulnerabilities that were once considered beyond the reach of drug discovery.
Applying New Chemistry to Cancer Research
The technology is already being applied to some of cancer’s most challenging questions.
One of the early projects in Jones’s laboratory focuses on acute myeloid leukemia (AML), including aggressive forms of the disease that are prone to relapse. Using a newly developed chemistry platform, Jones and his team have created a molecule that selectively engages a protein involved in leukemia biology, giving researchers a new way to determine whether blocking that protein could help slow leukemia growth.
The compound is currently being evaluated in laboratory models of AML. While the work remains in its early stages, it provides important proof of concept that the technologies developed in Jones’s lab can be used to access proteins that have previously been beyond the reach of traditional drug discovery approaches.
These advances developed in Jones’s laboratory are also creating new opportunities for collaboration across Dana-Farber. Researchers studying tumor biology and cancer immunotherapy frequently identify proteins that appear to play important roles in cancer, but often lack the tools needed to determine exactly how those proteins function—or whether they could be targeted therapeutically.
Working with investigators including David Barbie, MD, and Kai Wucherpfennig, MD, PhD, Jones develops specialized chemical probes that allow researchers to study these proteins in greater detail. These tools can reveal how specific proteins help tumors grow, evade the immune system, or resist treatment, while also helping determine whether they may represent promising targets for future therapies.
In this way, Jones’s laboratory serves as a bridge between biological discovery and drug development. As Dana-Farber scientists uncover new cancer mechanisms, his team can develop the chemistry needed to investigate them and assess their therapeutic potential.
“The biology guides us,” Jones says. “As we identify important targets, we can develop the chemistry needed to address them.”
His collaboration with Barbie has received support from the Claudia Adams Barr Program in Innovative Basic Cancer Research at Dana-Farber, while his collaboration with Wucherpfennig recently received the Melanoma Research Alliance Team Science Award.
From Discovery to Translation
For Jones, one of the most rewarding aspects of working at Dana-Farber is the close connection between scientific discovery and patient care.
“You have a much stronger connection to patients at a place like Dana-Farber,” he says. “You’re collaborating with world-leading cancer biologists and clinicians who are treating patients every day.”
That proximity helps keep the ultimate goal in focus. While the technologies emerging from Jones’s laboratory remain in the preclinical stage and may take years to translate into new medicines, they are designed to address challenges that patients face today, from treatment resistance to cancers that lack effective treatment options.
By opening access to targets that have historically been beyond the reach of traditional drug discovery, the research could transform how scientists pursue some of cancer’s hardest-to-drug vulnerabilities.
“If we’re successful,” Jones says, “we’ll be able to bring entirely new classes of targets into reach and create therapeutic opportunities that simply weren’t possible before.”
Team Members: Lyn Jones, PhD, Kai Wucherpfennig, MD, PhD, David Barbie, MD.
Team Members
Kai W. Wucherpfennig, MD, PhD
Chair, Cancer Immunology and Virology, Dana-Farber
Professor of Immunology, Harvard Medical School
David Barbie, MD
Chief, Thoracic Oncology
Jane Rodgers Chair, Dana-Farber
Professor of Medicine, Harvard Medical School
