Four-stranded anticancer DNA
Cylene Pharmaceuticals licenses Quarfloxin and related anticancer quadruplex technologies to TetraGene
Hurley, arenowned medicinal chemist who served for 18 years as editor of the AmericanChemical Society's Journal of MedicinalChemistry, was the scientific founder and CSO of Cyternex (now CylenePharmaceuticals) from 2001 to 2006, where he was well-acquainted with Cylene'swork with quadruplex-targeting technology. Now, TetraGene is developingsmall-molecule drugs aimed at highly validated cancer-causing genes, bydirectly targeting G-quadruplex structures in genomic DNA. TetraGene has theoption 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 Iclinical trials, and Hurley expects TetraGene to exercise its option by the endof October 2013.
"This agreement is a clear win for both organizations," saysDr. William G. Rice, president and CEO of Cylene Pharmaceuticals. "TetraGene iswell placed to advance Quarfloxin through the clinic and to capture exclusiveworldwide rights to the quadruplex-targeting technologies. Cylene will receivestandard industry payments as the quadruplex program progresses, and we willcontinue to focus our in-house development efforts on CX-5461, ourclinical-stage Pol I inhibitor that activates the p53 tumor suppressorselectively in cancer cells and not normal cells."
Also, Cylene is exploiting CK2-dependent pathways, which hasenabled the creation of the first-in-class, Phase II-ready CX-4945 agent andCX-8184, the second-generation agent, that can serve as the drugs of choice inrational drug combinations for improved treatment outcomes against many cancerindications, the company believes.
"The agreement between TetraGene and Cylene immediatelyprovides us with access to a clinical-stage drug," Hurley notes. "G-quadruplexstructures have been known as test-tube oddities for 50 years, but for most ofthat time, unequivocal evidence for their natural existence in cells and aclearer definition of their biological roles have been lacking."
Recently, however, researchers have provided confirmation ofthe presence of G-quadruplex structures in human telomeres—the repetitivenucleotide sequence found at the end of the chromosome—thus adding directconfirmation to some already persuasive arguments supporting G-quadruplexformation in this genomic region, Hurley notes.
"The validity of drug targeting G-quadruplex DNA andmodulating expression of cancer genes has dramatically increased in the lastfew years, and our team is uniquely positioned to take advantage of these newinsights," he states.
Hurley considers the ability to shut off oncogenes usingsmall molecules to be the "holy grail" in medicinal chemistry. Simply put,duplex DNA activates transcription while the quadruplex form turns offtranscription. Recently, he notes, a group at Cambridge demonstrated thatpyridostatin, a G-quadruplex-binding small molecule, increases the measurablepresence of genomic G-quadruplex DNA nearly five-fold.
"This highly significant result is proof of principle that asmall-molecule drug can disrupt the equilibrium between duplex and G-quadruplexDNA within the human genome," Hurley and co-author Adam Siddiqui-Jain wrote inthe March issue of Nature Chemistry."This equilibrium has long been proposed as an essential mechanism for regulatingtranscription of various oncogenes—genes that have the potential to causecancer—that contain G-quadruplex-forming elements. These data argue that,provided sufficient selectivity between different G-quadruplexes can beachieved, it should be possible to create small-molecule drugs capable ofaltering the G-quadruplex/duplex DNA equilibrium to regulate a specificbiological process, such as the inhibition of oncogene expression," theyconclude.