Lead Inventors:
Liang Tong, Ph.D.; Javed A. Khan, Ph.D.; Xiao Tao
Cell proliferation studies and diabetes drug development:
The enzyme nicotinamide phosphoribosyltransferase (NMPRTase, Nampt, PBEF, visfatin) is an essential component of the NAD+ biosynthesis pathway. NAD+ has diverse roles in cell biology and physiology, and multiple enzymes such as PARP1, sirtuins, and ADP-ribosyl cyclase use NAD+ as a substrate. NAD+ biosynthesis/salvage may be required to maintain cellular NAD+ levels. The NMPRTase inhibitor FK866 (APO866) depletes intracellular NAD+ levels in tumor cells and induces their apoptosis. The structure of NMPRTase with and without bound ligand is a potential source of information for designing new compounds that can modulate a wide variety of clinically relevant processes such as cell proliferation and diabetes.
Crystal structures of NMPRTase alone and with ligand allow design of new drugs:
This invention encompasses crystal structures of NMPRTase alone and with ligand. The three-dimensional structures of human NMPRTase alone and bound with ligand allow the design of a wide range of compounds or therapeutics. Methods for designing compounds to inhibit enzyme activity are included.
Applications:
• Design of NMPRTase inhibitors
• Treatments for Cancer
• Treatments for Diabetes
• Treatments for Ageing-related diseases
Advantages:
• Both bound and unbound structures are known
• Homology in human and mouse NMPRTases makes this widely applicable
Patent Status: Patent Pending (US20080020413A1) ~ see link below.
Licensing Status: Available for Sponsored Research Support
Publications: Khan JA, Tao X, Tong L. Molecular basis for the inhibition of human NMPRTase, a novel target for anticancer agents.
Nature Struct Mol Biol. (2006) 13(7):582-8.