Abstract 2717: DMH1, a small molecule inhibitor of BMP type I receptors, suppresses growth and invasion of lung cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily and their biological activity is mediated by the formation of heterodimeric complexes of BMP type I and type II receptors of serine/threonine kinases. BMPs play an important role in regulating cell proliferation, differentiation and migration, processes that are involved in carcinogenesis of many types of cancer. BMP-2 has been shown overexpressed in human non-small cell lung cancer (NSCLC) and enhances lung tumorigenesis, suggesting that blocking the BMP signaling may be an effective therapeutic approach for NSCLC. Although previous work demonstrated that known protein-based BMP antagonists such as Noggin may reduce lung tumor growth, their clinical application could be limited by short half-lives and poor intra-tumor delivery. In a previous zebrafish embryo-based structure and activity study, we identified DMH1, a highly selective small molecule inhibitor which specifically antagonize the intracellular kinase domains of BMP type I receptors, the critical mediators of BMP signaling. In the present study, we found that DMH1 potently reduced lung cell proliferation, promoted cell death, and decreased cell migration and invasion in vitro by blocking the BMP signaling, as indicated by the reduction of Smad 1/5/8 phosphorylation and gene expression of Id1, Id2 and Id3 in A549 and H460 cells. In an in vivo study, treatment by intraperitoneal injection of DMH1 (5 mg/kg) for four weeks significantly reduced the growth of A549-derived xenograft in SCID mice. In conclusion, our study indicates that small molecule inhibitors of BMP type I receptors may offer a promising novel therapeutic strategy for lung cancer. Citation Format: Ying Huang, Rachel Lee, Andy Chang, Jeffery Fan, Chantelle Labib, Cyrus Parsa, Robert Orlando, Bradley Andresen, Jijun Hao. DMH1, a small molecule inhibitor of BMP type I receptors, suppresses growth and invasion of lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2717. doi:10.1158/1538-7445.AM2014-2717