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

Abstract

The bone morphogenetic protein (BMP) pathway is highly conserved and plays central roles in health and disease. The quality and quantity of its signaling outputs are regulated at multiple levels, offering pharmacological options for targeted modulation. Both target-centric and phenotypic drug discovery (PDD) approaches were applied to identify small-molecule BMP inhibitors and stimulators. In this Review, we accumulated and systematically classified the different reported chemotypes based on their targets as well as modes-of-action, and herein we illustrate the discovery history of selected candidates. A comprehensive summary of available biochemical, cellular, and in vivo activities is provided for the most relevant BMP modulators, along with recommendations on their preferred use as chemical probes to study BMP-related (patho)physiological processes. There are a number of high-quality probes used as BMP inhibitors that potently and selectively interrogate the kinase activities of distinct type I (16 chemotypes available) and type II receptors (3 chemotypes available). In contrast, only a few high-quality BMP stimulator modalities have been introduced to the field due to a lack of profound target knowledge. FK506-derived macrolides such as calcineurin-sparing FKBP12 inhibitors currently represent the best-characterized chemical tools for direct activation of BMP-SMAD signaling at the receptor level. However, several PDD campaigns succeeded in expanding the druggable space of BMP stimulators. Albeit the majority of them do not entirely fulfill the strict chemical probe criteria, many chemotypes exhibit unique and unrecognized mechanisms as pathway potentiators or synergizers, serving as valuable pharmacological tools for BMP perturbation.

Discovery of Two Highly Selective Structurally Orthogonal Chemical Probes for Activin Receptor-like Kinases 1 and 2

“…Therefore, they represent highly selective chemical tools applicable in mechanistic studies of ALK1/ALK2-related signaling pathways that have been implicated in the development of many different diseases . M U1700 and M4K2234 represent a valuable addition to the small-molecule tool set of BMP modulators, and can be used for further pharmacological target validation of ALK1/2 for treatment of diseases such as DMG, FOP, MS or anemia of inflammation, along with other (pre)clinically profiled inhibitors. − The probe MU1700 is envisioned to be particularly suitable for neurological studies as it can pass through the blood-brain barrier and shows an exceptionally high accumulation in the brain. Based on its characteristics, the compounds MU1700 and M4K2234 have recently been reviewed and made available by the Structural Genomics Consortium as the state-of-the art chemical probes for ALK1/2 (). ,,, …”

Emerging Landscape of Osteogenesis Imperfecta Pathogenesis and Therapeutic Approaches

“…The BMP signaling system, crucial for bone formation, has also been explored in OI treatment. − Recombinant BMP-2-loaded silk fibroin microspheres have shown promise in enhancing bone growth in OI-modeled animals . Chemical modalities that act as mimetics or activators of BMP signaling are being explored, with some promising examples showing potential for bone regeneration, such as ventromorphin, PD-407824, and the newly discovered FK506 derivatives …”

“…While these developments offer exciting possibilities for modulating the BMP pathway and potentially serving as treatment alternatives for conditions like OI, it is important to note that these compounds are still in the preclinical stage. Clinical trials and FDA approval would be necessary to establish their safety, efficacy, and suitability for human use.…”