Potent, Easy to Use Targeted Toxins as Anti-Tumor Agents
Description of Invention:
The invention discloses synthesis and use of novel derivatives of 2-[2'-(2-aminoethyl)-2-methyl-ethyl]-l,2-dihydro-6-methoxy-3H-dibenz-[de,h]isoquinoline-l,3-dione as targeted anti-tumor agents. The use of targeted toxin conjugates with anti-cancer antibodies, such as herceptin, is increasing. Based on a comparison with the structurally complex toxins, such as DM1, available in the market, these novel toxins are more stable in circulation, thus making the toxin-conjugates more tumor-selective and less toxic. As such, these compounds are superior alternatives to the existing toxins.
The invention describes a potent and easy to synthesize toxin that can be used for generating a variety of prodrugs. These compounds can be attached to a ligand that recognizes a receptor on cancer cells, or to a peptide that is cleaved by tumor-specific proteases. The compounds are topoisomerase inhibitors and are mechanistically different from DM1 that targets tubulin.
The structure of the toxin allows it to be modified with a peptide linker that is stable, but rapidly cleaved in lysosomes after the compound is specifically taken up by cancer cells.
Applications:
The compounds can be used for preparation of a variety of potent anti-cancer agents with low systemic toxicity.
Advantages:
Easy to prepare
Structural features make these compounds more stable in circulation
Toxin conjugates are more tumor-selective and less toxic
Benefits:
600,000 cancer deaths occurred in 2006 in spite of advances in cancer therapeutics. A major limitation of current therapeutics is their toxic side effects. This technology can effectively treat cancer with low systemic toxicity and thus improve overall survival and quality of life of patients suffering from cancer. The current cancer chemotherapeutic market is valued at $42 billion and expected to grow.
Development Status: In vitro studies are completed and in vivo animal model studies are ongoing.
Inventors: Nadya I. Tarasova (NCI) Marcin D. Dyba (NCI) Christopher J. Michejda (NCI)
Patent Status:
DHHS Reference No. E-160-2006/0 --
U.S. Provisional Application No. 60/844,027 filed 12 Sep 2006
PCT Application No. PCT/US2007/078233 filed 12 Sep 2007, which published as WO 2008/033891 on 20 Mar 2008
Portfolios: Cancer
Cancer -Therapeutics-Immunoconjugates-Toxins Cancer -Therapeutics-Conventional Chemotherapy Cancer -Therapeutics
For Additional Information Please Contact: Adaku Nwachukwu J.D.
NIH Office of Technology Transfer
6011 Executive Blvd, Suite 325
Rockville, MD 20852-3804
Phone: 301 435-5560
Email: madua@mail.nih.gov
Fax: 301 402-0220
