Newly synthesized compounds can starve multiple myeloma—a rare form of blood cancer—to death, according to a series of studies using patient samples.
The new compounds offer “a new strategy for attacking multiple myeloma…”
Tumor cells, including those of the largely fatal plasma cell malignancy multiple myeloma, thrive on glucose. In this cancer, the tumor co-opts the GLUT4 protein, a vital glucose transporter, for its own proliferation and survival. The new compounds antagonized the transporter, helping to starve the cancer cells to death.
“Inhibiting a glucose transporter would be a new strategy for attacking multiple myeloma,” says Gary Schiltz, deputy director of the Center for Molecular Innovation and Drug Discovery (CMIDD) at Northwestern University, a research professor in pharmacology, and a corresponding author of the paper.
“Our ability to conduct molecular modeling and computational chemistry to support the design and synthesis of these compounds exemplifies the center’s ability to facilitate the translation of basic scientific discoveries into therapeutic candidates,” he says.
After the new compounds were synthesized at CMIDD, they went to Mala Shanmugam from Emory University and Paul Hruz from Washington University in St. Louis for testing in different biological assays to determine the compound’s ability to antagonize the GLUT4 glucose transporter.
Medicinal chemists at CMIDD used the resulting data to design and synthesize additional analogs of the compounds in an effort to optimize their targeting of GLUT4, while limiting effects on other proteins, including those in the GLUT family.
“One of the benefits of modeling is that it can be done relatively inexpensively and quickly, while making a significant impact,” says Schiltz. “We can quickly generate compounds that act against the target we are interested in, giving us a rapid foothold on the optimization process.”
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Rama Mishra, a cheminformaticist who applies computer and informational techniques to chemistry, applied his molecular modeling expertise to evaluate the binding of their GLUT4 antagonists to the protein and inform the design of new analogs with improved potency and selectivity for inhibiting GLUT4. This structure-based design approach is a powerful technique in modern medicinal chemistry because it allows for rapid evaluation of potential compounds computationally prior to their synthesis, which is often very labor-intensive.
“Integrating the biological data with the modeling data provides increased confidence that we are able to accurately characterize the binding of our small molecule to the target protein,” Schiltz says.
In coming months, the research group will improve the compound’s potency and eventually evaluate its pharmacogenetics—how a person’s genetic makeup may alter response to the drug.
“Mala has had terrific success so far in using patient samples to show that the compounds are effective at selectively killing the cancerous cells while sparing healthy ones,” Schiltz says.
“We’ve also determined that the new compound can work in concert with existing therapies, making the path forward a bit easier and promising,” he adds.
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The researchers report their findings in the European Journal of Medicinal Chemistry.
Source: Roger Anderson for Northwestern University
