New Structural Information on Quadruplex DNA Motif Offers Insight into Therapeutic Inhibition in Cancer
San Diego, Calif. – Jul 21, 2004
Reported today in the Journal of the American Chemical Society
Cylene Pharmaceuticals and its collaborators at the University of Arizona announced today the publication of an article that provides evidence that a quadruplex that regulates expression of the c-Myc oncogene can adopt different parallel-loop isomers. Findings were published in the Journal of the American Chemical Society (Vol. 126, No. 28) and entitled, “The Dynamic Character of the G-Quadruplex Element in the c-MYC Promoter and Modification by TMPyP4,” (J.Seenisamy, et. al.).
To better understand the structural basis for drug-induced lowering of c-Myc gene expression, a quadruplex-forming DNA sequence in the regulatory region of the c-Myc oncogene was used to elucidate the structures of both the naturally occurring G-quadruplex and its complex with a ligand. The G-quadruplex DNA motif, a critical part of the silencer element for the c-Myc promoter, was shown to occur as a dynamic mixture of four parallel-loop isomers. Upon incubation with the ligand, G-quadruplex parallel-loop isomers adjust their structure to a mixture of parallel/antiparallel G-quadruplex structures.
“The discovery that G-quadruplexes adopt a dynamic equilibrium among four parallel-loop isomers accounts for the unusually high stability of these naturally occurring DNA motifs and the tight regulation of c-Myc expression,” said Laurence H. Hurley, D.Sc., Howard J. Schaeffer Chair in Pharmaceutical Sciences at the University of Arizona College of Pharmacy and co-founder of Cylene Pharmaceuticals. “The shift in quadruplex structure to a mixture of parallel/antiparallel-loop isomers upon ligand binding provides important information into how these and other types of molecules inhibit c-Myc expression.”
“Quadruplex stabilization with a small molecule Oncogene Inhibitor, such as Cylene’s lead candidate CX-3543, silences oncogene expression by targeting a sub-class of parallel-type quadruplexes that regulate the expression of the VEGF and c-Myc oncogenes, ” said Tom Farrell, COO of Cylene Pharmaceuticals. “Detailed structural information on these quadruplexes gives insight into the mechanism of inhibition, provides structural information for Cylene’s drug discovery approach, and accelerates further design of next-generation Oncogene Inhibitor compounds.”
About Cylene Pharmaceuticals, Inc. (www.cylenepharma.com) Cylene Pharmaceuticals, Inc. is a privately-held pharmaceutical company dedicated to the discovery, development and commercialization of first-in-class small molecule drugs to treat life-threatening diseases, with a particular emphasis in oncology. Cylene’s pipeline is led by CX-3543, a VEGF/c-Myc Oncogene Inhibitor currently in preclinical development. CX-3543 and other molecules in the pipeline originate from the company’s proprietary platform, which directs small molecules at molecular targets that regulate the expression of key oncogenes. The company is establishing its leadership position in small molecule regulation of oncogene expression by commercializing the pioneering work of two Cylene founders, Professors Laurence Hurley and Daniel Von Hoff.
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