Design and Synthesis of Carbazolomaleimides and Morphogenic Natural Product-Inspired Compounds as Novel BMP Stimulators

Pluripotent stem cells can differentiate into virtually any cell type of the human body, making them a valuable tool in regenerative medicine and drug discovery. However, achieving targeted differentiation requires a profound understanding of the biology that guides cell fate decisions. In this context, chemical probes serve as valuable tools for investigating and modulating growth factor-mediated signaling.

In a stem cell-based, phenotypic screen probing Bone Morphogenetic Protein (BMP)-dependent aspects during early embryogenesis and osteogenesis, indoyl maleimides and the natural product-inspired derivative IM1 were identified as potential BMP stimulators.

Optimization of the indoyl maleimide cluster yielded carbazolomaleimide 2b with enhanced osteogenic potency. Mechanistic studies revealed that 2b induces an osteogenic morphology by targeting noncanonical BMP signaling, in part via GSK3β inhibition. When combined with canonical BMP potentiators, 2b synergistically amplified BMP-dependent osteogenic outputs, highlighting the potential of dual-targeting strategies. Thus, 2b serves as a new and promising tool for modulating noncanonical BMP signaling.

Following the structure elucidation of IM1, a diastereospecific, 8-step diversity-oriented synthesis was established, yielding 25 novel IM1 derivatives. This SAR collection enabled the identification of crucial structural, conformational, and stereochemical features essential for BMP activity. Optical resolution of the most active diastereomers yielded four enantiomers with highly stereospecific BMP activity. Both active and inactive enantiomers serve as a high-quality chemical probe set for target deconvolution and represent a significant expansion of the molecular BMP toolbox, advancing our understanding of BMP signaling in health and disease.

Rechte

Nutzung und Vervielfältigung:


CC BY-NC-ND 4.0

Bitte beachten Sie, dass einzelne Bestandteile der Publikation anderweitigen Lizenz- bzw. urheberrechtlichen Bedingungen unterliegen können.

Zitieren

Zitierform:
Zitierform konnte nicht geladen werden.