Synthetic lipopeptide inhibitors of RAS oncoproteins

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.

Competitive Advantages:

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

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)