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Synthetic Macrolides Inhibit Breast Cancer Migration

Posted Jun 13 2010 5:00pm

Description of Invention:
This technology relates to the synthesis of several novel macrocylic compounds (macrolides), built upon a quinic acid-containing scaffold, which are potent inhibitors of tumor cell migration. Specifically, the new molecules have been shown to inhibit breast cancer cell migration in vitro.

Tumor metastasis or cell migration is a multi-step process in which primary tumor cells spread or migrate by invading adjacent tissues and/or metastasizing to distance sites. Thus, one approach to cancer treatment may be the inhibition of tumor migration. The initial observation that migrastatin, a macrolide natural product first isolated from a Streptomycete, inhibits tumor cell migration gave rise to the synthesis of the analogs with increased potency and tumor cell selectivity reported here.

These compounds may be the basis for new antimetastatic and antiangiogenic drugs. Some of the novel macrolides that have been designed and synthesized inhibit tumor cell migration with low nanomolar to sub-micromolar IC50 values via a mechanism that appears to be similar to that of migrastatin and its analogs. The synthetic protocol used is straight forward and relatively high yielding, and has the potential to be further simplified.

The new compounds and methods may be used to treat a pathologic condition that may be ameliorated by inhibiting or decreasing cell migration or metastasis, to decrease anchorage-dependent growth of tumor cells, or to treat any pathologic condition characterized by neovascularization.

The new molecules have been shown to inhibit breast cancer cell migration in vitro. Breast cancer is the most common female cancer in the United States, the second most common cause of death in women and the main cause of death in women ages 45 to 55. Despite early diagnosis and treatment, recurrence of the cancer including distant tumor growth or metastases is common. Accordingly, there is a need for compounds, such as those described in this invention, that inhibit cell migration and angiogenesis.

Development Status:
  • Synthesis of several analogs has been carried out
  • Migration of breast cancer cells has been demonstrated to be inhibited in vitro at sub-micromolar IC50 values.
  • The lead compound has been demonstrated not to be cytotoxic at levels up to 100 micromolar.
  • Scaled up synthesis of the most potent macrolide is presently being scaled up to unable for future testing in a mouse model of breast cancer.

Carole A Bewley Clore (NIDDK)
Belhu B Metaferia (NIDDK)

Patent Status:
HHS, Reference No. E-098-2007/0
US, Application No. 12/526,477 filed 07 Aug 2009

Relevant Publication:
  1. BB Metaferia, L Chen, HL Baker, XY Huang, CA Bewley. Synthetic macrolides that inhibit breast cancer cell migration in vitro. J Am Chem Soc. 2007 Mar 7;129(9):2434-2435. [ PubMed abs ]

Licensing Status:
Available for licensing.

Collaborative Research Opportunity:
The National Institute of Diabetes and Digestive and Kidney Diseases, Laboratory of Bioorganic Chemistry, is seeking parties interested in collaborative research to develop larger scale syntheses of the most potent macrolides and/or analogs thereof, and the conduct toxicology and other efficacy studies related to these macrolides. Please contact Dr. Carole Bewley at or Rochelle S. Blaustein at for more information.

Cancer - Therapeutics
In-vitro Data

For Additional Information Please Contact:
Whitney Hastings
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States
Phone: 301-451-7337
Fax: 301-402-0220

Ref No: 1562

Updated: 06/2010

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