Five Questions with Jay Bradner
As associate director of the Broad’s Center for the Science of Therapeutics (CSofT), award-winning hematologist at Dana-Farber Cancer Institute, and a recognized pioneer in open-source drug discovery (not that he would admit to it), Jay Bradner is something of a rock star in the field of chemical biology.
In 2010, Bradner secured his reputation as an innovator when, rather than guarding his discovery of a breakthrough small molecule, he began sharing the compound with other scientists in the field. The molecule, JQ1, inhibited a family of proteins known as bromodomians, and showed promise for blocking the growth of certain cancer cells. Since 2010, the Bradner lab has shared 15 different compounds with more than 450 laboratories worldwide.
This month, Bradner unveiled his latest breakthrough: a new chemical technology platform to destroy proteins in cancer cells. The finding, published online in Science Express, could pave the way for new inhibitors for previously “undruggable” targets.
For this edition of ‘Five Questions,’ we visited Bradner at his gleaming new “garage shop of discovery” in Boston’s Longwood Medical Area to discuss this new technology, the role of medicinal chemistry in the age of CRISPR, and the lessons he’s learned about open-source drug discovery.
Q1: CRISPR and immunotherapy seem to be grabbing all the headlines lately. Where does medicinal chemistry fit these days?
Like everyone in the cancer community, I’ve been following the advances in immune checkpoint therapy and the clinical opportunity of CRISPR with real admiration and excitement. It turns out we’re also witnessing one of the most productive windows in the history of cancer medicinal chemistry. Breakthrough small-molecule therapeutics developed to target altered gene products or activated pathways are showing profound activity in clinical trials for chronic lymphocytic leukemia, Waldenstrom’s, acute myeloid leukemia (AML), and breast cancer. Epigenetic drug development alone has an opportunity to yield three breakthrough drugs for AML in the next 3 years. That would make three more than have been realized in nearly 20 years. You can’t help but be excited and optimistic.
Q2: Which of your projects has you most excited these days?
These days, we’re all about targeted protein degradation in my lab. Despite all the progress in medicinal chemistry I just described, we are still lacking direct-acting inhibitors for many of the most important cancer targets. It’s not for lack of trying. Some protein targets have biochemical active sites or protein binding sites that are not amenable to direct binding by a small molecule. We’ve experienced this in my lab, developing bromodomain inhibitors as cancer therapy. We have become very good at drugging bromodomains, but sometimes the bromodomain is not the active site of the molecule. What then?
To address this shortcoming, we created a chemical platform technology to convert molecules that bind their targets into molecules that promote the degradation of their targets. In that way, an inactive binder might be modified to become a highly active protein destroyer. We had great success using this approach to get the rapid loss of critical cancer-related proteins in aggressive models of acute leukemia.
Back in the lab, we are optimizing these compounds as drug molecules while developing degraders for 24 pressing targets in cancer and non-malignant diseases. There are a number of very cool potential applications of this approach, which could produce a lot of very powerful chemical tools and experimental methods for the scientific community.
Photo courtesy of
Dana-Farber Cancer Institute
Q3: What kind of resistance did you encounter when you first proposed the idea of sharing JQ1?
To Dana-Farber’s credit, there was little resistance. The profound burden of cancer and the complexity of cancer genetics both call not only for new therapeutic technologies but also new strategies for therapeutic discovery.
With that said, they raised some important questions: Would the open invitation to access technologies from our lab threaten the priority of our science? Would commercialization opportunities, and therefore clinical translation, be jeopardized? If it catches on, is it scalable? We had (and have) no firm answers, but we committed to study our experience and collect data on outcomes. In these first seven years of my laboratory, we have provided about 15 chemical probes to more than 450 laboratories worldwide. In the area of BET bromodomains, we have observed a doubling of scholarly publications coincident with the availability of the JQ1 chemical probe, a phenomenon that has been previously described with kinase inhibitors and the patent literature. Last year, four molecules transitioned to human clinical investigation, including our own drug-like derivative. This year, we expect four more companies to enter clinical trials. For my lab, open-source drug discovery has been an expensive, but eye-opening undertaking.
Q4: What is the biggest lesson you learned from sharing JQ1?
It’s funny - there is no obligation for recipient laboratories to report research findings, but almost everyone does. Labs may reach out to request more material, perhaps for in vivo studies, but most write or call just to share their incredible findings.
We’ve also experienced how powerful chemical probes are in target validation. In response to a questionnaire we sent laboratories that received JQ1, 50% of investigators responded that their work with the compound led to a disease-specific clinical opportunity.
Finally, we learned that compounds are powerful vehicles of experimental reproducibility, a major issue in science today. In two research areas, two or more groups have simultaneously published mutually supportive stories on BET bromodomain biology using JQ1.
Beyond these lessons, the open-source strategy has been a wonderful introduction to research fields that I might not have otherwise had an opportunity to access. We have fantastic collaborators in cardiovascular disease, tissue remodeling and fibrosis, and reproductive biology. Though my group focuses on chromatin and chemical biology largely in the area of cancer, these collaborations have broadened our research horizons significantly.
Q5: What are your thoughts on collaborating with pharmaceutical companies? What role should the Broad play?
Drug development is a team sport. If I’m being honest, at our best in my lab we are tinkering: with new technologies, with mechanistic or therapeutic hypotheses. About once a year, our work reaches a point where we become impatient to bring an idea to patients, convinced the molecule or approach could alleviate the burden of cancer. When this happens we need to become ideal collaborators for industry. We simply don’t have the requisite expertise or resources required to manufacture a molecule as a drug substance, defend it with a regulatory document, execute a contract with medical centers, or sponsor and lead human clinical trials. Working together with the local biopharmaceutical community has, for me, been a very positive and respectful experience.
At the Broad, we have a real opportunity to move the needle in disease-specific therapeutics. The Broad’s chemistry efforts, led by Stuart Schreiber, were built with a long-term vision, akin to the physics community organizing a generational strategy to characterize the Higgs-Boson.
Already, there are three centers for therapeutic development at the Broad—the Center for the Science of Therapeutics, the Center for the Development of Therapeutics, and the Stanley Center for Psychiatric Disease. Only an institution that is unabashedly committed to drug discovery would build out three therapeutic centers. As ever, the Broad is boldly determined to develop next-generation genome medicines. I am excited to be a member of this community at this important time.