Phenotypic Drug Discovery Campaigns Expand the Chemical and Druggable Space of BMP Stimulators

The tools of modern medicine have evolved from small-molecules, through biologicals, to entire cells. The emerging discipline of regenerative medicine holds unparalleled potential to transform healthcare and change our perspective on chronic illness. Pluripotent stem cells present a key enabling technology that has opened new paths in the study and treatment of disease. Here, chemical probes provide powerful tools to investigate and manipulate the signaling pathways that orchestrate cell fate decisions on the molecular level. Bone morphogenetic protein (BMP) is a growth factor that regulates physiology from embryonic patterning to adulthood and is associated with various diseases. Despite fundamental physiological roles, the BMP signaling pathway is still not fully understood and chemical tools probing BMP are lacking. Moreover, classic drug discovery has struggled to produce high-quality probes that effectively activate growth factor signaling pathways. To address this issue a phenotypic discovery platform, employing murine embryonic stem cells as an authentic yet high-throughput compatible model, was developed to selectively probe BMP signaling. Chromenone 1 and CGS15943 were identified as novel BMP stimulating chemotypes with unique molecular mechanisms. Chromenone 1 acts through a kinase-independent feedback loop, enhancing BMP signaling by inhibiting the competing TGFβ pathway. CGS15943 was found to target CK1 and PI3K isoforms, uncovering a previously unknown link to BMP. Furthermore, strategies were developed to expedite the discovery of BMP stimulators. A proof-of-concept screen identified Compound 2b demonstrating the feasibility of targeting noncanonical BMP signaling to synergistically amplify cellular responses. The herein described chemical modalities expand the chemical and druggable space of BMP stimulators, constituting a significant addition to the pharmacological BMP toolbox and illustrate the unique power of phenotypic drug discovery.


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