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EXECUTIVE SUMMARY
CDC42-Associated Kinase (ACK) as a Therapeutic Target for Ras-Induced Cancer
SUMMARY: Dr. Shah A. Nur-E-Kamal, in the Department of Pharmacology at the University of Medicine & Dentistry of New Jersey (UMDNJ) has validated CDC42-associated kinase (ACK) as an attractive therapeutic target for the discovery of new agents for the treatment of Ras-induced cancers such as brain, breast and prostate. Several early-stage lead compounds against this target have already been identified and structural optimization studies are in progress. Siuta Consulting has been retained by UMDNJ to identify pharmaceutical or biotechnology company partners for the further development of this technology. BACKGROUND: Activation of Ras GTPase function has been shown to be associated with various types of cancer. This knowledge invites the possibility of targeting Ras to develop novel cancer chemotherapeutic agents. However, activation of Ras GTPase results in the activation of multiple signaling pathways that are involved in controlling growth and differentiation of mammalian cells. Thus targeting Ras directly may have deleterious effects on non-cancer cells. TECHNOLOGY: This technology is based on the discovery that Ras signaling for transformation transduces through the activated CDC42-associated kinase and validates ACK as an attractive therapeutic target for Ras-induced cancer. Dr. Nur-E-Kamal has found that CDC42 and activated CDC42 associated kinase act downstream of Ras signaling in cancer cells. To prove this, the expression of ACK was knocked down using siRNA in v-Ha-Ras NIH 3T3 transformed cells. Transfection of ACK siRNA knocked down the expression of ACK in a dose-dependent manner in v-Ha-Ras transformed NIH 3T3 and parental NIH 3T3 cells. Transfection of ACK siRNA inhibited the growth of v-Ha-Ras transformed NIH 3T3 cells in a dose-dependent manner and did not affect the growth of the parental NIH 3T3 cells. Additionally, ACK-deficiency in the v-Ha-Ras transformed cells induced PARP cleavage, caused fragmentation of chromosomal DNA and caused cleavage of inhibitor of caspase activated DNase (ICAD) resulting in apoptosis. Therefore Ras signals transduced through ACK protect v-Ha-Ras transformed cells from apoptosis. PD158780, a known tyrosine kinase inhibitor, was found to inhibit the kinase activity of ACK in vitro and affect the growth of v-Ha-Ras transformed NIH3T3 cells in a dose-dependent manner. Thus the Ras-CDC42-ACK signaling pathway is required for survival of Ras-transformed mammalian cells and ACK is an attractive target to develop a chemotherapeutic agent for treatment of Ras-induced cancer. Employing structure-based design approaches, several early-stage drug leads have been identified for further development. These simple molecules inhibit V-Ha-Ras-transformed NIH 3T3 cells in a dose-dependent manner. Time-course experiments reveal that treatment by these lead compounds at 25μM inhibited the growth of v-Ha-Ras-transformed cells by >50% in 24 hours. Ongoing studies suggest that these compounds are potent and selective ACK inhibitors with potential utility as therapeutic agents against Ras-induced cancer. Further structural optimization of these molecules is currently in progress.This invention presents a validated target for development of novel chemotherapeutic agents against Ras-induced cancers that allows inhibition of Ras signaling specifically in cancer. CDC42-ACK can be used as a target in search of novel therapeutic agents for Ras-induced cancers, such as brain, breast and prostate. PATENT STATUS: A United States Provisional Patent Application was filed in August 2005. LICENSE TERMS: UMDNJ is seeking pharmaceutical or biotechnology company partners for the further development of this technology. |