INNOVATION 

Rationale- geranylgeranylation of Ras proteins is a key escape pathway for oncogenic cells treated with farnesyl transferase inhibitors (FTIs). Small molecule antagonists of GGTaseI are therefore promising candidates for fully blocking activation of Ras.

Leads- Both UC22 and UC23 are drug-like compounds that are likely to be have good oral bioavalability based on their structures and functional groups.

In vitro potency- UC22 and UC23 were assayed for their ability to inhibit GGTAase-I geranylgeranylation of RhoA and KRas4B. IC50's are UC22 (0.5 uM RhoA, 0.9 uM KRas4B) and UC23 (0.3 uM RhoA, 2 uM KRas4B).

Specificity- both UC22 and UC23 have been shown to be specific for GGTI versus GGTII and FTI

Cell growth inhibitory potency- UC22 and UC23 were assayed for their ability to inhibit proliferation of human cell lines MDA-MB231 and MiaPaCa2. IC50's are UC22 (50uM in MDA-MB231 and 20 uM MiaPaCa2) and UC23 (10 uM in MDA-MB231 and 8 uM in MiaPaCa2). Cell cycle arrest at the G1 phase was observed in these studies.

Target- The molecular target is known and there is SAR and a crystal structure which will aid in further medicinal chemistry.

DEVELOPMENT-TO-DATE 

UCLA is seeking commercial partners who are strategically interested in keeping abreast of this work or who may be interested in a strategic collaboration and/or in-licensing for further development of these leads through to an IND.

Reference: UCLA Case No. 2006-357