A new class of anticancer drugs that inhibit two or more molecular targets at once, which maximizes therapeutic efficiency and safety was described by a research team from the University of California San Diego School of Medicine and Moores Cancer Center, which in collaboration with colleagues at Rady Children's Hospital-San Diego, the University of Colorado School of Medicine and SignalRx, a San Diego-based biopharmaceutical company.
The research was published in the journal Proceedings of the National Academy of Sciences (PNAS).
‘A potentially new class of drugs which can hit multiple cancer cell targets was found to boost efficacy and safety.’
A regulatory gene MYC, controls the expression of other genes that code transcription factors or proteins which are involved in a number of fundamental cellular processes. It is the most frequently altered gene in cancer which makes it an attractive target for cancer therapies. The gene has proved to be very complicated and an elusive target.
"Most anti-cancer drugs have a single target. They try to do one thing, such as block a single receptor or signaling pathway," said study co-senior author Donald L. Durden, MD, PhD, professor in the Department of Pediatrics at UC San Diego School of Medicine and associate director for pediatric oncology at Moores Cancer Center at UC San Diego Health. "This paper is proof-of-concept of a completely different mode of drug discovery clearly separated from the standard practice of one drug, one target."
Specifically, Durden and colleagues engineered a small molecule called SF2523 in silico, using molecular modeling crystal structure and nuclear magnetic resonance imaging, to simultaneously disrupt two key MYC-mediating factors that promote cancer cell growth. Those two factors are PI3K, an enzyme, and BRD4, a protein.
In cell and mouse models, they found SF2523 concomitantly inhibited PI3K and BRD4, blocking MYC activation and expression and markedly inhibiting cancer growth and metastasis, with improved efficacy and less toxicity to the host.
"This is a 'first in class' approach to achieve a maximum inhibition of MYC in the treatment of the multitude of cancers known to be driven by the MYC oncogene," said Durden. "These findings suggest that dual-activity inhibitors are a highly promising lead compound for developing new anticancer therapeutics."