Glycomimetic Drugs: An Untapped Source of Novel Therapeutics
Glycomimetic Drugs: An Untapped Source of Novel Therapeutics Now in Clinical Trials for Hematologic Malignancies
Dr. John L Magnani, Chief Science Officer, Co-founder, Vice President and Director, GlycoMimetics, Inc.
Story by Supriya Venigalla
Dr. John L. Magnani and his team at GlycoMimetics, Inc., in Gaithersburg, Maryland, have harnessed the power of glycomimetics to design new treatments for certain cancers and sickle cell disease.
“Glycomimetics are molecules similar in structure to carbohydrates. They fit very precisely in the binding site of a protein,” said Dr. Michael Pierce, director of the UGA Cancer Center. “John’s been going after the binding proteins called selectins.”
Selectins are versatile players involved with inflammation, the regulation of defensive lymphocytes, and the binding of malignant cells in the bone marrow.
Magnani’s team exploits this to maximize the proportion of cancer cells that chemotherapy can eradicate. “The cells lodged in the bone marrow cannot be treated, so they need to be flushed out. And that’s what glycomimetics do – inhibit their binding and coax them to come out into the circulation,” said Magnani.
Magnani knows his target well, as he was the discoverer of Sialyl-Lewisa, a tumor marker for colon cancer (CA19-9) and a binding ligand for E-selectin. He and his colleagues used this information to develop potent selectin inhibitors and start a biotech company.
In May 2015, GlycoMimetics, Inc., began a phase 1/2 clinical trial of an E-selectin antagonist, GMI-1271, as a potential treatment for acute myeloid leukemia (AML) in combination with chemotherapy. The team found that this new glycomimetic enhances the efficacy of AML killing by chemotherapy, disrupts adhesion involved in cell adhesion-mediated drug resistance (CAMDR), and protects hematopoietic stem cells (HSCs) in a quiescent niche.
It was not easy to get to this point: the very first attempts to turn carbohydrates into clinically useful drugs were unsuccessful. Carbohydrates are not drug-like molecules, and they degrade quickly.
Instead of trying to work with whole molecules, Magnani took a different path.
“What we do is take that property of a carbohydrate that gives it specific recognition for its receptor, and we mimic that with traditional small molecule drugs that have the right pharmacokinetics,” said Magnani. “We then improve the binding affinity by using the laws of thermodynamics and stabilize the core structure.”
This innovative approach led not only to GMI-1271, now being tested in AML patients, but also to a second drug with an entirely different indication.
Rivipansel, originally dubbed GMI-1070, is now an FDA-approved treatment for vaso-occlusive crisis in patients with sickle cell disease. These excruciatingly painful episodes were previously treated only with supportive therapy--hydration, pain control, and hospitalization.
But in a three-year, phase 2 clinical trial, Rivipansel treatment reduced the duration of vaso-occlusive crisis, shortened hospital stays, and cut the need for narcotic pain relief.
The FDA gave it a fast-track approval, and in 2011 Pfizer licensed the drug in a $340 million agreement with GlycoMimetics. The giant pharmaceutical corporation is now responsible for further clinical development of Rivipansel.
“This is pioneering work. The exciting thing for glycobiology is that this is proof of concept, that glycomimetics can work as drugs,” said Pierce. “It’s just the beginning of recognition by the pharmaceutical companies that glycomimetics can be used as drugs and can be successful.”
Magnani sees glycomimetics as the future of cancer immunotherapy.
“Right now we see glycomimetics as an adjuvant to chemotherapy. But we’re looking ways of getting our T-cell responses much better with a glycomimetic,” said Magnani.
Magnani reviewed his team’s progress during the 2015 UGA Conference on Drug Discovery.
Supriya Venigalla, MD, is a second-year M.P.H. student at UGA’s College of Public Health and a reporter for Graduate Newsroom.