Identification Of Small Molecule Agonists/Activators Of Bmp-2, 4, 7 Signaling

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Medulloblastoma (MB) is the most common malignant pediatric brain tumor. MB is a cancer of the cerebellum that occurs in children between the ages of 3 and 7. Human MBs have been classified into four subgroups, two of which harbor mutations in pathways that regulate normal development of the brain: Sonic Hedgehog/Patched (Shh/Ptch) (25%) and Wnt (15%). Our laboratory found that the bone morphogenetic proteins (BMP-2, 4, 7) antagonize Shh signaling by inducing the irreversible differentiation of MB cells into neurons leaving normal post-mitotic neurons intact. We designed a cell-based luciferase assay in which a human carcinoma cell line, C33A, expressed a multimerized BMP-responsive element from the Id1 promoter linked to luciferase. We then screened 3,488 compounds with known bioactivity and 31,441 compounds from the St. Jude diversity library for small molecule agonists of the BMP-2, 4, 7 signaling cascade. To date, 14 candidate compounds induced luciferase activity in a dose-dependent manner. Secondary screens showed that these small molecules induce P-Smad1/5/8 and Id2 expression in a dose-dependent manner in C33A cells by western blotting analysis, and alkaline phosphatase (ALP) activity which is a quantitative measure for the differentiation of C2C12 mouse myoblasts into osteoblasts. One of the compounds ventralized zebrafish embryos. Ongoing efforts are focused on understanding the mechanism of activation of BMP-4 signaling by these small molecule agonists. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4522. doi:10.1158/1538-7445.AM2011-4522