“The development of multi-target drugs may be a promising strategy to overcome tumor resistance and prolong the therapeutic benefits for patients,” said co-author Nagi Ayad, Ph.D., a member of the Cancer Epigenetics Program at Sylvester and associate professor of psychiatry and behavioral sciences at the Miller School. “Inhibition of cancer-promoting kinases is an established therapeutic strategy, and targeting cancer-promoting pathways, such as BRD4, one of the bromo and extra-terminal (BET) proteins, also shows promise.” His research is supported by NIH grant R01NS067289.
Stephan Schürer, Ph.D., associate professor of molecular and cellular pharmacology, and interim Director of the Drug Discovery program at the UM Center for Computational Science (CCS), added, “We have performed recent studies that suggest our computational screening pipeline may be broadly applicable for identifying dual kinase/BET inhibitors with potential for treating various cancers.”
Other co-authors of the study, “Large-Scale Computational Screening Identifies First in Class Multitarget Inhibitor of EGFR Kinase and BRD4,” were Saurabh Mehta, Ph.D., assistant scientist for drug discovery at CCS, and Bryce K. Allen, a doctoral student at CCS who is also in the pharmacology track in the Programs in Biomedical Sciences. Two researchers at the Moffitt Cancer Center in Tampa also contributed to the work.
“Using advanced computation, we can leverage large-scale small molecule-protein interaction, systems biology ‘omics,’ and chemistry data to accelerate the development of new compounds for complex diseases,” said Schürer, whose research at CCS was funded by the National Institutes of Health Common Fund Library of Integrated Network-based Cellular Signatures (LINCS) and Big Data to Knowledge (BD2K) programs. The Women’s Cancer Association also provided funding to identify dual inhibitors for acute leukemia.
To identify the new cancer inhibitor, the researchers screened more than 6 million commercially available compounds, selected 24 for testing, and identified several novel BRD4 inhibitors, including the first dual EGFR-BRD4 inhibitor. Those findings were then confirmed by wet laboratory experiments.
“There are several advantages of targeting both pathways with one compound,” said Ayad. “First of all, the tumor cell has less chance of evading an inhibited pathway, prolonging the effectiveness of anti-cancer treatment. It’s like putting two molecular roadblocks in front of the cancer cell, rather than just one.”
A dual-action inhibitor also avoids the issues of multi-drug interactions that can impact the patient’s ability to tolerate cancer treatment. “Having one compound that does the work of two avoids that problem,” Ayad said. “It also makes it easier to change drugs if necessary during the course of treatment.”
Schürer noted that the next step is to optimize the identified dual-inhibitor into viable lead compounds for glioblastoma, a type of brain tumor, and potentially for ERBB2 positive breast cancer. “Future studies will look for targets in leukemia and other forms of cancer,” he said. “By using this scalable screening approach, and computationally driven medicinal chemistry, which we are setting up right now in collaboration with Sylvester, we hope to develop other dual-action compounds that show promise in fighting this disease.”
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