Abstract 1746: Discovery and evaluation of a small molecule KIFC1 inhibitor for breast cancer treatment

Abstract

Abstract Historically, drugs used in the treatment of certain cancers may cause damage to healthy cells while affecting cancer cells. Therefore, finding compounds that are specific toward cancer cells only is still a high priority in the search for new therapies. In contrast with normal cells, most cancer cells contain multiple centrosomes which are associated with genome instability and tumorigenesis. Cancer cells can avoid multipolar mitosis which can cause cell death by clustering the extra centrosomes into two spindle poles, thereby enabling bipolar division. Kinesin-like protein KIFC1 plays a critical role in centrosome clustering in cancer cells, but is not essential for normal cell survival. Therefore, targeting KIFC1 may give some insight into how a novel therapy can selectively target only cancer cells. Here, we report that KIFC1 up-regulation is a frequent event in human breast cancer and that KIFC1 is highly expressed in all 8 tested human breast cancer cell lines, but is absent in normal human mammary epithelial cells and weakly expressed in 2 human lung fibroblast lines. We also found that depletion of KIFC1 in breast cancer cells induced cell death. From a high throughput screen of 30,000 compounds, we identified a small molecule KIFC1 inhibitor, SRH06, which has an enzymatic IC50 value of 6.5 μM versus KIFC1 and binds directly to KIFC1 without interacting with the microtubule. Results from our computer modeling studies suggested that SRH06 binds to a novel allosteric site on KIFC1 that appears suitable for the development of selective KIFC1 inhibitors. Importantly, SRH06 prevented bipolar clustering of extra-centrosomes in breast cancer cells and significantly reduced colony formation and cell viability, but was less toxic to normal LL47 fibroblasts. Therefore, SRH06 provides a very valuable tool to study the biological function of KIFC1 and serves as a potential lead for the development of a novel therapeutic agent for the treatment of breast cancer. Citation Format: Wei Zhang, Ling Zhai, Wenyan Lu, Yimin Wang, Vandana V. Gupta, Indira Padmalayam, Robert J. Bostwick, Lucile White, Ross Larry, Joseph Maddry, Sam Ananthan, Mark Suto, Bo Xu, Rongbao Li, Yonghe Li. Discovery and evaluation of a small molecule KIFC1 inhibitor for breast cancer treatment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1746. doi:10.1158/1538-7445.AM2015-1746