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.

Lysosomal degradation of ACVR1-Activin complexes negatively regulates signaling of Activins and Bone Morphogenetic Proteins

“…Our findings have implications for therapeutic approaches targeting ACVR1 signaling in FOP and other indications. Various approaches are under investigation 36 , including inhibition of Activin A 15 , inhibition of ACVR1 kinase [37][38][39] , inhibition of ACVR1 using blocking antibodies 4,16,[40][41][42] , and siRNA-mediated reduction of ACVR1 expression 43 . Our findings predict that at the molecular level these approaches will have different outcomes.…”

Small-Molecule Probes as Pharmacological Tools for the Bone Morphogenetic Protein Signaling Pathway

“…Compound 16 (Figure A) was developed from a SAR series of novel pyrazolo­[4,3- d ]­pyrimidines as a remarkably potent, selective, and orally bioavailable inhibitor of ALK2 in rats . In fact, its pyrazolo­pyrimidine scaffold is reminiscent of the first-in-class BMP inhibitor Dorsomorphin .…”

“…62 Compound 16 (Figure 2A) was developed from a SAR series of novel pyrazolo [4,3-d]pyrimidines as a remarkably potent, selective, and orally bioavailable inhibitor of ALK2 in rats. 63 In fact, its pyrazolopyrimidine scaffold is reminiscent of the first-inclass BMP inhibitor Dorsomorphin. Nevertheless, a detailed kinome profile for extended characterization is still lacking for final evaluation of chemical probe qualities compared to those of other available BMPR-I inhibitors.…”

Discovery of Orally Bioavailable FGFR2/FGFR3 Dual Inhibitors via Structure-Guided Scaffold Repurposing Approach

“…17,18 During our search for a suitable starting point for next-generation FGFR kinase inhibitors, we became interested in compound 1 (Figure 2), which was reported previously as a potent and selective in vivo tool for ALK2 inhibition (IC 50 = 0.98 nM). 19 Broad kinase panel screening data obtained from the off-target characterization of 1 demonstrated a clean profile with only modest activity toward FGFR3 (IC 50 = 178 nM). Given the unique chemical structure of 1 in comparison to all other reported FGFR inhibitors, we further profiled this molecule against the remaining FGFR isoforms in enzymatic biochemical assays.…”

“…Furthermore, currently approved FGFR inhibitors share a common structural motif (i.e., the 3,5-dimethoxyphenyl group) that fills a hydrophobic pocket in the region near the gatekeeper residue of the FGFR kinase domain (Figure ). As a result, clinical resistance to current FGFR-targeted therapy via gatekeeper mutation has been observed and suggests the need to identify a new chemotype that does not target the gatekeeper region. , During our search for a suitable starting point for next-generation FGFR kinase inhibitors, we became interested in compound 1 (Figure ), which was reported previously as a potent and selective in vivo tool for ALK2 inhibition (IC 50 = 0.98 nM) . Broad kinase panel screening data obtained from the off-target characterization of 1 demonstrated a clean profile with only modest activity toward FGFR3 (IC 50 = 178 nM).…”