Discovery of a novel class of benzimidazoles as highly effective agonists of bone morphogenetic protein (BMP) receptor signaling

Abstract

Increasing or restoring Bone Morphogenetic Protein receptor signaling is an effective therapy for conditions such as bone fracture and pulmonary arterial hypertension. However, direct use of recombinant BMPs has encountered significant obstacles. Moreover, synthetic, full agonists of BMP receptor signaling have yet to be identified. Here, we report the discovery of a novel class of indolyl-benzimidazoles, synthesized using a one-pot synthetic methodology, which appear to mimic the biochemical and functional activity of BMPs. The first-in-series compounds, SY-LB-35 and SY-LB-57, stimulated significant increases in cell number and cell viability in the C2C12 myoblast cell line. Cell cycle analysis revealed that these compounds induced a shift toward proliferative phases. SY-LB-35 and SY-LB-57 stimulated canonical Smad and non-canonical PI3K/Akt, ERK, p38 and JNK intracellular signaling pathways, similar to BMP2-stimulated responses. Importantly, increases in Smad phosphorylation and cell viability were dependent on type I BMP receptor activity. Thus, these compounds robustly activate intracellular signaling in a BMP receptor-dependent manner and may signify the first known, full agonists of BMP receptor signaling. Moreover, discovery of small molecule activators of BMP pathways, which can be efficiently formulated and targeted to diseased or damaged areas, could potentially substitute recombinant BMPs for treatment of BMP-related pathologies.

Therapeutic Intervention of Neuroinflammatory Alzheimer Disease Model by Inhibition of Classical Complement Pathway with the Use of Anti-C1r Loaded Exosomes

“…Whole cell lysates or tissue homogenates (50 μg) were diluted with 4X Laemmli sample buffer to final 1X dilution and western blot procedure was conducted according to Najafi et al [ 40 ]. The C1r primary antibody (1:1000) and the HRP-conjugated secondary antibody (1:1000) were used.…”

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

“…Ventromorphins and Sb4 were utilized by other groups following their publication, although with mixed success and partly in concentrations strongly deviating from their original description (Table ). SY-LB-35 was more recently disclosed, and while the pharmacophore-fusion approach is an interesting concept, functional characterization in a BMP-dependent context and determination of pathway selectivity are missing.…”

“…Ventromorphins and Sb4 were utilized by other groups following their publication, although with mixed success and partly in concentrations strongly deviating from their original description (Table 4). SY-LB-35 was more recently disclosed, and while the pharmacophore-fusion approach is an interesting concept, 130 functional characterization in a BMPdependent context and determination of pathway selectivity are missing. The carbazolomaleimide PD407824 (Figure 5B) is a known pan-kinase inhibitor 131,132 and was identified as a BMP stimulator from a cell-based screen of 4000 compounds in C2C12 myoblasts using a BRE-luc reporter for readout.…”