Wortmannin Conjugates and Uses Thereof (BIDMC 952)

Category:    Drug Delivery

KeyWords:  Cancer;  Chemotherapy;  Method;  

BIDMC ID:    952

Abstract:

Overactivity of the signal transduction molecule phosphoinositide 3-OH kinase (PI3K) has a significant role in the progression of cancer and inflammatory disease. In fact, PI3K mutations have been increasingly identified in 50% of solid tumors and 30% of breast cancers. With this link to cancer, PI3K is rapidly becoming a central target for anti-cancer therapy. Wortmannin, a specific PI3K inhibitor has potent anti-proliferative and anti-inflammatory activities but has been unsuitable for clinical applications due to its inherent toxicity and instability in cells. To overcome these limitations, the world-renowned expert in PI3K, Dr. Lew Cantley and leading radiologist Dr. Lee Josephson have identified and synthesized novel PI3K inhibitors suitable for cancer treatment. These leading scientists have developed Wortmannin conjugates for both drug delivery and classical medicinal chemistry. The Wortmannin conjugates or pro-drugs can be delivered as targeted or slow release forms of Wortmannin that may inhibit PI3K in tissues more selectively than the parent Wortmannin. These pro-drugs conjugated to specific antibodies and peptides achieve targeted delivery of Wortmannin resulting in localized concentrations of the drug and reducing systemic toxicity. This targeted approach affords the additional advantage of delivering both Wortmannin and other anti-proliferative or anti-inflammatory molecules to effect inhibition of PI3K and other molecular pathways. The development of PI3K inhibitors is essential for the treatment of diseases in which inhibiting cellular proliferation or inflammation is beneficial.

Inventor:   Hushan Yuan, Ji Luo, Ralph Weissleder, Lewis Cantley and Lee Josephson Dr. Cantley is a world-renowned scientist for first cloning and identifying PI3 kinase. Dr. Josephson is a leading expert in radiology at Massachusetts General Hospital.

Commercial Opportunity:

PI3K inhibitors are potential therapeutic drugs for treating cancer and inflammatory diseases. Wortmannin conjugates may be delivered locally or systemically making it a treatment for a broad spectrum of acute and chronic indications. Some diseases that would benefit from PI3K inhibition are breast and prostate cancer, anaphylactic reactions, spinal chord trauma, shock, allergic reactions and arthritis.

Competitive Advantages:

Cancer is the second leading cause of death in the United States. An estimated 500,000 people will die each year to the ravaging effects of cancer. The standard care for treating cancer patients are chemotherapeutic drugs that are non-specific, toxic and with long-term use lead to cellular drug resistance. Wortmannin conjugates are potential drugs that achieve slow- or controlled-release forms of Wortmannin with improved bioavailability, better stability and reduced toxicity. The advantage of targeted-delivery to specific tissue or cell types using Wortmannin conjugates is to achieve high, localized concentrations while reducing systemic toxicity of Wortmannin. Wortmannin also has potent anti-inflamamtory activity. Millions of patients suffer from the debilitating effects of rheumatoid arthritis. Developing an effective, safe therapy to treat arthritis and other inflammatory disease would be extremely beneficial.

Related Publications:

H. Yuan, Ji Luo, R. Weissleder, L. Cantley and L. Josephson, December 2005 Wortmannnin-C20 conjugates generate Wortmannin  Journal of Medicinal Chemistry (in press)

L. Cantley, 2002. The Phosphoinositide 3-Kinase Pathway May 31;296 Science.  (5573):1655-7. (PI3 Kinase Pathway)

State of Development:

Research to synthesize and characterize the efficacy of Wortmannin conjugates is ongoing.   A partnership opportunity is available for the discovery and subsequent development of novel therapeutics for cancer treatment.  Technology licensing opportunity is also available.    

Related Technology URL:

Patent Status:

Provisional Application submitted September 1, 2005

TVO Contact Info:
     Christine Jost
     Associate Director TVO
     cjost@bidmc.harvard.edu
     Phone: 617-667-4239   Fax: 617-667-0646

     Beth Israel Deaconess Medical Center
     Technology Ventures Office  Room: BR-0200
     330 Brookline Avenue
     Boston, MA 02215