ras Oncogene Inhibitors

Summary Activated ras genes have been associated with a number of human cancers. An activated ras gene, H-ras-1, was the first non-viral oncogene discovered. Several other human ras proto-onco genes have subsequently been identified including H-ras-2, K-ras-1, K-ras-2, and N-ras. Activated K-ras genes have been detected in pre-malignant neoplasms of the human colon and in human pre-leukemia.

The ras proteins and ras-like proteins, including R-ras, RAS2, rap-2, and phoB, have a conserved carboxyl-terminal -CAAX motif . This motif is involved in a series of post-translational modifications including polyisoprenylation, carboxyl-terminal proteolysis, and carboxyl-methylation. Analysis of ras gene mutations has shown that inhibition of these modifications (by mutation) blocks both membrane localization of ras gene product and transformation of the cell (Willumsen et al., EMBO J. 3:2581; Gutierrez et al., EMBO J. 8:1093, 1989).

Further work, buy analysis of in vitro translated K-ras, demonstrated that farnesylated, non-proteolysed, non-methylated K-ras associates inefficiently with cell membranes. These observations led Harvard Medical School researchers, under the leadership of Dr. Robert Rando, to look for inhibitors of these processes. He found a series of small molecules that inhibit C-terminal methlyation or proteolysis. He demonstrated the effectiveness of these inhibitors in both enzymatic assays and cell growth experiments, using HL-60 cells, which have an activated ras gene.

ADVANTAGES:

Small molecule therapeutic

Validated in cell growth assay

INTELLECTUAL PROPERTY: U.S. rights are available under US patents 6,015,877, 5,202,456 and 5,789, 541.

Applications Cancer therapeutic.

Two separate inventions: endoprotease inhibitor and methylation inhibitor. For Further Information Please Contact the Director of Business Development Michal Preminger Email: michal_preminger@hms.harvard.edu Telephone: (617) 432-0920

Inventor(s): Rando, Robert R

Type of Offer: Licensing



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