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Synthetic lipopeptide inhibitors of RAS oncoproteins

Summary
It is well known that overactive Ras signaling is linked to many forms of cancer, and despite intensive efforts worldwide to develop effective inhibitors of Ras, to date there is no anti-Ras inhibitor in clinical use. Researchers at the NCI’s Cancer and Inflammation Program, in collaboration with scientists at Vanderbilt University and the University of Illinois in Chicago, have identified a number of small peptidomimetic compounds that bind to Ras proteins with nanomolar affinity. NCI’s Cancer and Inflammation Program seeks partners interested in licensing or co-development of synthetic, highly potent cell-permeable inhibitors of Ras that bind to the protein directly.
NIH Reference Number
E-293-2010
Product Type
Keywords
  • colon
  • lung
  • multiple myeloma
  • pancreatic cancer
  • thyroid cancer
  • Ras
Collaboration Opportunity
This invention is available for licensing and co-development.
Contact
Description of Technology

It is well known that overactive Ras signaling is linked to many forms of cancer, and despite intensive efforts worldwide to develop effective inhibitors of Ras, to date there is no anti-Ras inhibitor in clinical use.

Researchers at the NCI’s Cancer and Inflammation Program, in collaboration with scientists at Vanderbilt University and the University of Illinois in Chicago, have identified a number of small peptidomimetic compounds that bind to Ras proteins with nanomolar affinity.  The development of compounds was based on two previously unknown mechanisms of Ras regulation uncovered due collaborative efforts of the three groups. The researchers have found that hypervariable regions (HVR) of some isoforms of Ras proteins function as negative regulators of Ras activity. Rational design lead to generation of metabolically stable cell-permeable analogs of HVRs with much improved binding affinity and anti-tumor activity.  The second class of inhibitory compounds targets Ras dimerization interface. Compounds inhibit RAS-dependent growth of cancer cells at low nanomolar and subnanomolar concentrations.

In vitro data indicate that the inhibitors are effective at inhibiting growth in a number of cancer cell lines including lung cancer. In addition, in vivo data indidate that the inhibitors are effective at  inhibiting tumor growth in mouse xenograft models. 

The inventors are interested in collaborations to help optimize PK/PD properties of Ras inhibitors and conduct preclinical in vivo studies.

Potential Commercial Applications

- Novel cancer therapeutic (prostate cancer, colon cancer, pancreatic cancer, ovarian cancer, lung cancer, breast cancer, thyroid cancer, leukemia, bladder cancer, salivary gland cancer, melanoma, myeloid malignancy, or germ cell tumors)

Competitive Advantages

- Synthetic compounds binding to Ras proteins with high affinity
- Cell permeable peptidomimetics
- Membrane-anchored inhibitors

Development Stage
Publications

Jang, H., et al. [PMID: 25713064]

Patent Status
  • U.S. Patent Issued: U.S. Patent Number 9328142
  • U.S. Patent Filed: U.S. Patent Application Number 15/015,940, Filed 04 Feb 2016
Therapeutic Area
Updated
Wednesday, August 31, 2016