Abstract B39: A novel series of substituted indene derivatives that potently and selectively inhibit growth of tumor cells harboring mutant Ras
Authors: Chen Xi , Lee Kevin J. , Gary Bernard D. , Canzoneri Joshua C. , Fajardo Alexandra M. , Sigler Sara C. , Ramirez-Alcantara Veronica , Zhu Bing , Piazza Gary A. , Keeton Adam B. 
Published: May 2015

Background and Significance: Mutations in the Ras family of proto-oncogenes are relatively common in cancer. Activating Ras mutations occur de novo in approximately one third of cancers and may also develop in tumors that become resistant to targeted therapies, especially against receptor tyrosine kinase inhibitors. The NSAID, sulindac and certain non-cyclooxygenase derivatives are known to have chemopreventive activity and have been reported to be particularly effective against tumors and cell lines with Ras mutations. Although Ras mutations have been known for many years, they remain a target that is poorly represented by current cancer therapeutics. In fact, the target has been described as “undruggable” because of the high affinity of Ras for its substrate, GTP.

Methods & Results: Using a synthetic lethal approach, we screened a focused collection of compounds chemically related to sulindac. The screen identified a hit compound that potently and selectively inhibited the growth of tumor cell lines expressing mutant Ras (A-549 and MDA-MB231) compared with a tumor cell line bearing the wild-type Ras (HT-29). Follow-up experiments confirmed that tumor cells of several histotypes expressing mutant Ras were sensitive. The selectivity was also observed in a paired isogenic cell model system in which mutant Ras is artificially introduced (NRK, K-NRK). Based on this scaffold, we have synthesized a series of substituted indene compounds with increased selectivity for cancer cells with mutated Ras. Structure-activity relationships for potency and Ras selectivity are being explored within this series. We have identified highly potent compounds which inhibited growth with IC50 values in the low nM range. The compounds exhibited selectivity ranging between 10- to 500-fold for mutant Ras expressing cell lines. Studies demonstrating the mechanism of growth inhibition as well as studies to identify the molecular target of the prototype compound will be presented.

Conclusions: We have synthesized a novel series of compounds that potently inhibit the growth of cancer cell lines of several histotypes harboring Ras mutations. In contrast, tumor cells expressing wild-type Ras are relatively insensitive. This series represents a promising, targeted approach to treatment of cancers with this relatively commonly mutated oncogene.

This project is supported by NIH grant 5R01CA155638-02.

Citation Format: Xi Chen, Kevin J. Lee, Bernard D. Gary, Joshua C. Canzoneri, Alexandra M. Fajardo, Sara C. Sigler, Veronica Ramirez-Alcantara, Bing Zhu, Gary A. Piazza, Adam B. Keeton. A novel series of substituted indene derivatives that potently and selectively inhibit growth of tumor cells harboring mutant Ras. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B39. doi: 10.1158/1557-3125.RASONC14-B39