Discovery of Novel Pyrazolopyrimidines as Potent, Selective, and Orally Bioavailable Inhibitors of ALK2

Abstract

Activin receptor-like kinase 2 (ALK2) is a transmembrane kinase receptor that mediates the signaling of the members of the TGF-β superfamily. The aberrant activation of ALK2 has been linked to the rare genetic disorder fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG) that are associated with severely reduced life expectancy in pediatric patients. ALK2 has also been shown to play an essential role in iron metabolism by regulating hepcidin levels and affecting anemia of chronic disease. Thus, selective inhibition of ALK2 has emerged as a promising strategy for the treatment of multiple disorders. Herein, we report the discovery of a novel pyrazolopyrimidines series as highly potent, selective, and orally bioavailable inhibitors of ALK2. Structure-based drug design and systematic structure-activity relationship studies were employed to identify potent inhibitors displaying high selectivity against other ALK subtypes with good pharmacokinetic profiles.

Figure 1

Proposed binding mode of compound 5 in the ATP pocket of ALK2. (A) Interaction of 5 with ALK2 in the hinge region. (B) Side view showing the dimethylpiperidine moiety in proximity to the catalytic Lys235 and Asp354.