Phenotypic Discovery of Triazolo[1,5-c]quinazolines as a First-In- Class Bone Morphogenetic Protein Amplifier Chemotype

Phenotypic drug discovery (PDD) continues to fuel the research and development pipelines with first-in-class therapeutic modalities, but success rates critically depend on the quality of the underlying model system. Here, we employed a stem cell-based approach for the target-agnostic, yet pathway-centric discovery of small-molecule cytokine signaling activators to act as morphogens during development and regeneration. Unbiased screening identified triazolo[1,5-c]quinazolines as a new-in-class in vitro and in vivo active amplifier of the bone morphogenetic protein (BMP) pathway. Cellular BMP outputs were stimulated via enhanced and sustained availability of BMP-Smad proteins, strictly dependent on a minimal BMP input. Holistic target deconvolution unveiled a unique mechanism of dual targeting of casein kinase 1 and phosphatidyl inositol 3-kinase isoforms as key effectors for efficient amplification of osteogenic BMP signaling. This work underscores the asset of PDD to discover unrecognized polypharmacology signatures, in this case significantly expanding the chemical and druggable space of BMP modulators.

Automated summary

Phenotypic drug discovery is an important research approach, and its success relies on the quality of the underlying model system. In this study, a stem cell-based method was used to discover a new activator for the bone morphogenetic protein pathway. Through comprehensive target deconvolution, a unique dual targeting mechanism was revealed. This work expands the chemical and druggable space of BMP modulators.