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Protein Profiling Method Reveals Many Potential New Drug Targets

LA JOLLA, CA — July 31, 2017 — Scientists at The Scripps Research Institute (TSRI) have invented a versatile method for identifying proteins that can feasibly be targeted with drugs to treat disease.

Using the new method, published on July 31, 2017 in Nature Chemistry, the TSRI scientists identified more than 100 human proteins that are likely to be targetable with small molecule, pill-based drugs. Some of these proteins already have been implicated in diseases such as cancer, but only a minority were previously known to be “druggable.”

“This new protein profiling method allows us to expand the universe of proteins that can be targeted by small molecules, which in turn should encourage the development of new drugs as well as probes for studying protein biology,” said senior investigator Benjamin F. Cravatt, a professor of chemical biology at TSRI.

Determining whether a disease-related protein can react strongly with a small-molecule probe or candidate drug—in a way that alters its function—is often an essential first step in drug development. Yet broad methods for mapping this important property of proteins have been scarce. Thus, for most of the human repertoire of about 25,000 proteins, scientists simply don’t know which ones are druggable.

In response to that need, Cravatt and colleagues have been developing new methods to discover and map the sites on proteins where small-molecule probe can bind. In the past several years, for example, they have invented techniques for identifying druggable sites centered on cysteine or serine amino acids on proteins. With those methods, they have successfully revealed the druggability of hundreds of proteins, many of which had previously been thought un-druggable.

For the new study, the TSRI researchers sought to map druggable sites centered on lysine amino acids. As for cysteines and serines, Cravatt and colleagues found that lysine sites sometimes have a high degree of chemical reactivity, which makes them more likely to be involved in their protein’s function—and thus potentially good drug targets.

The high reactivity of some lysine sites also means that certain chemical compounds can make a certain type of extra-tight, effectively irreversible bond with them, known as a covalent bond. In principle, a drug molecule that can recognize such a reactive site on a protein and then bind covalently to it will be much more potent than a drug that binds more weakly and reversibly. Covalently binding drugs include old drugs such as aspirin and penicillin, as well as powerful new enzyme inhibitor drugs for treating cancers.

Cravatt and colleagues, including first authors Stephan M. Hacker and Keriann M. Backus, both postdoctoral research associates at the time of the study, started by identifying a chemical compound (pentynoic acid sulfotetrafluorophenyl ester) that can selectively and covalently bind to reactive lysines on proteins. The scientists then used the compound as a probe to characterize the reactivity of more than 4,000 lysines on proteins in human cells.

Of these lysines, 310 met criteria for being abnormally reactive. As expected, the scientists found that these hyper-reactive lysines were unusually likely to be located at functional sites on proteins.

In another experiment, a more direct test of druggability, the researchers used a library of small molecules —broadly representing potential drug molecules—to see which could compete with the probe in binding covalently to reactive lysines on human proteins. This test revealed 121 lysines in 113 proteins that were clearly targetable with small molecules, and thus are in principle targetable with candidate drug molecules.

For many of these proteins, the observed interactions with small molecules provided the first evidence of their druggability.

The proteins newly revealed to be druggable belong to a variety of functional classes, including enzymes that catalyze biochemical reactions, scaffold proteins that act as hubs for other protein signaling complexes, and transcription factors that regulate gene activity.

To demonstrate the potential usefulness of this method for drug discovery, the researchers selected several of these proteins and showed that the small molecules targeting these proteins also blocked the proteins’ functions.

In some cases, the small molecules turned out to work by inhibiting a protein’s enzyme activity—a very common mechanism for drugs. In other cases, they appeared to work in ways that have traditionally been considered challenging for small-molecule drugs. For example, in the case of the protein SIN3A, a regulator of gene transcription, the small molecule that covalently binds to its reactive lysine blocks the protein’s function by disrupting SIN3A’s interaction with another protein, TGIF1—an interaction implicated in some invasive breast cancers.

“More optimized compounds targeting that same reactive lysine in SIN3A might hinder cancer cell growth and malignancy, and thus might represent a starting point for drug development,” said Cravatt.

Having made this proof-of-principle demonstration, Cravatt and colleagues now plan a broader effort to discover small molecules that bind covalently to reactive lysines.

“We think this approach has the potential to substantially expand the map of the druggable human proteome,” Cravatt said.

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including two Nobel laureates and 20 members of the National Academies of Science, Engineering or Medicine—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. In October 2016, TSRI announced a strategic affiliation with the California Institute for Biomedical Research (Calibr), representing a renewed commitment to the discovery and development of new medicines to address unmet medical needs. For more information, see

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Benjamin F. Cravatt, Ph.D. (High-res image)