Identification of Maleimide-Fused Carbazoles as Novel Noncanonical Bone Morphogenetic Protein Synergizers.

Abstract

Morphogenic signaling pathways govern embryonic development and tissue homeostasis on the cellular level. Precise control of such signaling events paves the way for innovative therapeutic approaches in the field of regenerative medicine. In line with these notions, bone morphogenic protein (BMP) is a major osteogenic driver and pharmacological stimulation of BMP signaling holds supreme potential for diseases and defects of the skeleton. Efforts to identify small-molecule modalities that activate or potentiate the BMP pathway have primarily been focused on the canonical signaling cascade. Here, we describe the phenotypic identification and development of specific carbazolomaleimides 2 as novel noncanonical BMP synergizers with submicromolar osteogenic cellular potency. The devised chemical tools are characterized to specifically regulate Id gene expression in a SMAD-independent, yet highly BMP-dependent fashion. Mechanistic studies revealed that GSK3 inhibition and increased β-catenin levels are partly responsible for this activity. The utility of the new BMP synergizer profile was further exemplified by showing how the synergistic action of canonical and noncanonical BMP enhancers additively amplifies BMP-dependent osteogenic outputs. Carbazolomaleimide 2b serves as a new and unique pharmacological tool for the modulation and study of the BMP pathway.