Abstract 904: TP-0413 is a dual-specific inhibitor against Jak2 and Alk2 with therapeutic potential for treating anemia of chronic disease

Anemia of chronic disease is a debilitating condition commonly found in cancer patients. Studies suggest that this syndrome is largely the result of the body's production of hepcidin, a master regulator of human iron metabolism. TP-0413 is a small molecule that targets two important components of the hepcidin pathway, Janus Kinase 2 (Jak2) and Activin A receptor, type I (Alk-2). Jak2 facilitates hepcidin function by phosphorylating ferroportin upon hepcidin binding, inducing its degradation and thus preventing iron entry into plasma. Alk2 on the other hand, is a component of the signal transduction pathway that leads to hepcidin expression. Here we report on recent efforts aimed at further characterization of TP-0413. In biochemical assays TP-0413 inhibits Jak2 and Alk2 at 3.11 nM and 70 nM, respectively (IC50). In cell culture, HepG2 cells treated with TP-0413 exhibit reduced hepcidin levels, and TP-0413 is able to inhibit BMP-2 induction of hepcidin. Furthermore, TP-0413 ameliorates hypoferremia induced by LPS treatment in mice, and modulates cytokine levels in these animals. TP-0413 shows favorable drug-like properties in pharmacokinetic models, and further studies are being undertaken to advance TP-0413 towards clinical trials. Citation Format: Bret J. Stephens, Alexis Mollard, Lingyao Meng, David J. Bearss, Steven L. Warner. TP-0413 is a dual-specific inhibitor against Jak2 and Alk2 with therapeutic potential for treating anemia of chronic disease. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 904. doi:10.1158/1538-7445.AM2013-904