In future studies, we propose to utilize the ferret model of IAV infection to assess the therapeutic potential of SAP given that ferrets express abundant a-linked SA throughout the respiratory tractand human IAV strains infect ferrets without the need for prior adaptation. Such studies would provide important insight regarding the ability of SAP to ameliorate influenza disease severity and/ or virus transmission in a model that more accurately depicts many characteristics of human disease. Members of the transforming growth factor-betasuperfamily bind transmembrane receptor serine/threonine kinases to activate Smad and non-Smad pathways for the control of normal development and tissue repair. Ligand binding induces type II receptor phosphorylation of associated type I receptors, leading to Smad recruitment and phosphorylation by the type I receptor. The receptor-associated Smadssubsequently SCH727965 779353-01-4 assemble with co-Smad4 for nuclear transport and transcriptional activation. Small molecule inhibitors of the type I receptorshave proved to be valuable pharmacological tools to characterize TGF-b and BMP pathways in signaling, as well as stem cell biology. TGF-b inhibitors such as SB-431542 inhibit Smad2/3 phosphorylation by ALK4, ALK5 and ALK7, as well as non-classical Smad1/5 phosphorylation by ALK5. Conversely, inhibitors of BMP signaling have recently been described that specifically inhibit Smad1/5/8 phosphorylation by ALK1, ALK2, ALK3 and ALK6. Notably, these molecules have shown efficacy in a variety of disease models, including chronic anemia, prostate cancer, muscle wasting, heterotopic ossification, atherosclerosis and vascular calcification. While specific TGF-b inhibitors have been developed over many years, BMP inhibitor development remains at an early stage. New leads in this target area are desirable for several reasons. First, current work follows a single high throughput screen performed in the zebrafish system. Second, independent tool compounds are preferred for functional validation, whereas the screening hit dorsomorphin, and derivatives DMH1and LDN-193189, share the same pyrazolopyrimidine scaffold. Third, more selective compounds are needed to minimize unwanted off-target effects. Most importantly, there is an urgent need for selective ALK2 inhibitors to treat the debilitating bone disorder fibrodysplasia ossificans progressiva. FOP sufferers carry a gain of function mutation in the intracellular domain of ALK2, resulting in episodic bone formation in skeletal muscle and connective tissue that ultimately renders movement impossible. U0126 molecular weight Trauma and surgery only accelerate the condition, while biological inhibitors lacking cell penetrance are ineffective. As an alternative but 
complementary strategy to phenotypic screens, we used direct screening of recombinant human kinases to identify new inhibitor leads against ALK2. We report a novel BMP inhibitor scaffold, comprising a 2-aminopyridine core and a trimethoxyphenyl specificity group, which is both potent and selective. The identified inhibitor K02288 provides a new pharmacological tool to investigate the diversity of BMP signaling in both normal and pathobiology. The development of selective small molecule inhibitors of protein kinases presents a major challenge due to the high sequence conservation of the ATP pocket. Here we report a novel 2-aminopyridine inhibitor K02288 with potent and selective activity against type I BMP receptor kinases. The 2-aminopyridine group is an ATP-mimetic that binds the kinase hinge region through two conserved hydrogen bonds. Importantly, selective kinase inhibitors with this scaffold have been identified previously.