Florence Wagner

Florence Wagner

Vitals

Current affiliation: Broad Institute of MIT & Harvard

Age: 37

Ph.D. alma mater: North Carolina State University

Advice for young scientists: “If someone tells you that you cannot do something, show them how you can do it better.”

If I were an element, I would be: Oxygen. “Everyone needs a breath of fresh air.”

The field of psychiatric drug discovery needs a jump start. Not everyone responds to the available therapies, and those who do often have to deal with unmanageable side effects. Moreover, current drugs are all based on old biology: For example, the last time a truly novel drug for schizophrenia or bipolar disorder made it to market, Florence (Flo) Wagner hadn’t even been born.

She thinks it’s time for a reboot.

At the Stanley Center for Psychiatric Research at the Broad Institute of MIT & Harvard, where she is director of medicinal chemistry, Wagner and her colleagues take innovative approaches to go after some psychiatric targets that have stumped pharma. “Industry wouldn’t have touched a couple of the projects we’ve worked on,” says Edward Scolnick, chief scientist at the Stanley Center and a former president at Merck Research Laboratories. “But Flo is very confident in her abilities.”

Research at a glance


GSK3 is a possible target for bipolar disorder and other psychiatric disorders. Wagner’s team designed a molecule (BRD-1652) that selectively inhibits GSK3 and doesn't interact with other related enzymes, such as CDK2 and CDK9, outside the brain. Credit: Yang H. Ku/C&EN/Shutterstock/Wikimedia Commons


GSK3 is a possible target for bipolar disorder and other psychiatric disorders. Wagner’s team designed a molecule (BRD-1652) that selectively inhibits GSK3 and doesn’t interact with other related enzymes, such as CDK2 and CDK9, outside the brain.
Credit: Yang H. Ku/C&EN/Shutterstock/Wikimedia Commons

These targets have long eluded drug developers because they are extremely similar to related proteins that chemists want to avoid hitting. To design highly selective molecules, Wagner’s team starts with high-throughput screens of compounds in which the scientists look for compounds that are selective for their target relative to related proteins. The more typical approach is to search for molecules that are potent at hitting the target.

Recently, Wagner and her colleagues developed molecules that can selectively inhibit each of the two forms of an enzyme called glycogen synthase kinase 3 (GSK3), a possible target of the bipolar disorder treatment lithium. Previous inhibitors out of industry hit both forms of GSK3 and caused serious side effects in human studies. Wagner and her colleagues showed that selectively inhibiting either of the two forms avoided that toxicity in cells. The chemists now openly share these compounds with other scientists looking to understand the biology of GSK3 in other diseases.

Meanwhile, other Stanley Center scientists are studying the biological mechanisms underlying psychiatric disorders, efforts that will provide novel drug targets. “There won’t be a lack of targets to work on,” Wagner says. “With patients awaiting new treatments, we feel a duty to show that these novel targets could lead to effective therapies.”

Three key papers

“Inhibitors of Glycogen Synthase Kinase 3 with Exquisite Kinome-Wide Selectivity and Their Functional Effects”(ACS Chem. Biol. 2016, DOI: 10.1021/acschembio.6b00306)

“An Isochemogenic Set of Inhibitors To Define the Therapeutic Potential of Histone Deacetylases in β-Cell Protection” (ACS Chem. Biol. 2016, DOI: 10.1021/acschembio.5b00640)

“Kinetically Selective Inhibitors of Histone Deacetylase 2 (HDAC2) as Cognition Enhancers” (Chem. Sci. 2015, DOI: 10.1039/C4SC02130D)

Vitals

Current affiliation: Broad Institute of MIT & Harvard

Age: 37

Ph.D. alma mater: North Carolina State University

Advice for young scientists: “If someone tells you that you cannot do something, show them how you can do it better.”

If I were an element, I would be: Oxygen. “Everyone needs a breath of fresh air.”

Bozhi Tian