Four-stranded anticancer DNA
SALT LAKE CITY, Utah—Speaking over his cell phone from Jeddah, Saudi Arabia, where he is serving a brief stint as a guest lecturer, Dr. Laurence Hurley, TetraGene LLC's chief scientific officer (CSO), puts it succinctly: "We're making ourselves the quadruplex-targeting company." The springboard for TetraGene was the inking of an exclusive, worldwide option and license agreement with Cylene Pharmaceuticals Inc. that will allow TetraGene to advance the development of Quarfloxin and Cylene's associated anticancer quadruplex-targeting technologies. Cylene will receive an upfront fee, as well as potential milestone payments and royalties on product sales for the exclusive license.
Hurley, a renowned medicinal chemist who served for 18 years as editor of the American Chemical Society's Journal of Medicinal Chemistry, was the scientific founder and CSO of Cyternex (now Cylene Pharmaceuticals) from 2001 to 2006, where he was well-acquainted with Cylene's work with quadruplex-targeting technology. Now, TetraGene is developing small-molecule drugs aimed at highly validated cancer-causing genes, by directly targeting G-quadruplex structures in genomic DNA. TetraGene has the option to acquire worldwide rights to the technologies licensed from Cylene, which include the Phase II compound Quarfloxin and several registered patents. Quarfloxin has been demonstrated to be safe and well tolerated in Phase I clinical trials, and Hurley expects TetraGene to exercise its option by the end of October 2013.
"This agreement is a clear win for both organizations," says Dr. William G. Rice, president and CEO of Cylene Pharmaceuticals. "TetraGene is well placed to advance Quarfloxin through the clinic and to capture exclusive worldwide rights to the quadruplex-targeting technologies. Cylene will receive standard industry payments as the quadruplex program progresses, and we will continue to focus our in-house development efforts on CX-5461, our clinical-stage Pol I inhibitor that activates the p53 tumor suppressor selectively in cancer cells and not normal cells."
Also, Cylene is exploiting CK2- dependent pathways, which has enabled the creation of the first-in-class, Phase II-ready CX-4945 agent and CX-8184, the second-generation agent, that can serve as the drugs of choice in rational drug combinations for improved treatment outcomes against many cancer indications, the company believes.
"The agreement between TetraGene and Cylene immediately provides us with access to a clinical-stage drug," Hurley notes. "G-quadruplex structures have been known as test-tube oddities for 50 years, but for most of that time, unequivocal evidence for their natural existence in cells and a clearer definition of their biological roles have been lacking."
Recently, however, researchers have provided confirmation of the presence of G-quadruplex structures in human telomeres—the repetitive nucleotide sequence found at the end of the chromosome—thus adding direct confirmation to some already persuasive arguments supporting G-quadruplex formation in this genomic region, Hurley notes.
"The validity of drug targeting G-quadruplex DNA and modulating expression of cancer genes has dramatically increased in the last few years, and our team is uniquely positioned to take advantage of these new insights," he states.
Hurley considers the ability to shut off oncogenes using small molecules to be the "holy grail" in medicinal chemistry. Simply put, duplex DNA activates transcription while the quadruplex form turns off transcription. Recently, he notes, a group at Cambridge demonstrated that pyridostatin, a G-quadruplex-binding small molecule, increases the measurable presence of genomic G-quadruplex DNA nearly five-fold.
"This highly significant result is proof of principle that a small-molecule drug can disrupt the equilibrium between duplex and G-quadruplex DNA within the human genome," Hurley and co-author Adam Siddiqui-Jain wrote in the March issue of Nature Chemistry. "This equilibrium has long been proposed as an essential mechanism for regulating transcription of various oncogenes—genes that have the potential to cause cancer—that contain G-quadruplex-forming elements. These data argue that, provided sufficient selectivity between different G-quadruplexes can be achieved, it should be possible to create small-molecule drugs capable of altering the G- quadruplex/duplex DNA equilibrium to regulate a specific biological process, such as the inhibition of oncogene expression," they conclude.