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.