Preclinical activity of BC2059, a novel compound that degrades beta-catenin, in colon cancer models.

e14090 Background: BC2059 (BetaCat Pharmaceuticals) is a novel small molecule that degrades s-catenin in a proteosomally dependent manner in cancer cells. Methods: We tested the activity of BC2059 in vitro, in patient derived colon cancers in 3-dimensional cultures and in vivo using HT-29 xenografts. We also used a novel doxycycline driven siRNA model that downregulates s-catenin to test activity of BC2059. Results: BC2059 was highly active with IC90s in MTS assays (μM): SW480 (0.44), Colo205 (0.66), Colo201 (0.03), HT29 (0.92) and relatively inactive in SW48 (9.83) or L cells (normal) (4). In a 3-Dimensional culture system where we grew patient-derived colon cancer cells in a matrigel system and measured cell death by ethidium bromide exclusion, surprisingly, the average EC50 was 200 picomolar indicating that the compound was much more effective in patient derived samples. In matrigel tumor invasion assays, BC2059 demonstrated potent inhibition of tumor invasion. In HT-29 mouse xenografts, BC2059 series ...