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000619713 1001_ $$aWesseler, Fabian$$b0
000619713 245__ $$aPhenotypic Discovery of Triazolo[1,5- c ]quinazolines as a First-In-Class Bone Morphogenetic Protein Amplifier Chemotype
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000619713 520__ $$aPhenotypic 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.
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000619713 7001_ $$aLohmann, Stefan$$b1
000619713 7001_ $$aRiege, Daniel$$b2
000619713 7001_ $$aHalver, Jonas$$b3
000619713 7001_ $$aRoth, Aileen$$b4
000619713 7001_ $$aPichlo, Christian$$b5
000619713 7001_ $$aWeber, Sabrina$$b6
000619713 7001_ $$aTakamiya, Masanari$$b7
000619713 7001_ $$aMüller, Eva$$b8
000619713 7001_ $$aKetzel, Jana$$b9
000619713 7001_ $$aFlegel, Jana$$b10
000619713 7001_ $$aGihring, Adrian$$b11
000619713 7001_ $$aRastegar, Sepand$$b12
000619713 7001_ $$aBertrand, Jessica$$b13
000619713 7001_ $$aBaumann, Ulrich$$b14
000619713 7001_ $$aKnippschild, Uwe$$b15
000619713 7001_ $$00000-0003-1532-7826$$aPeifer, Christian$$b16
000619713 7001_ $$aSievers, Sonja$$b17
000619713 7001_ $$00000-0002-9606-7247$$aWaldmann, Herbert$$b18
000619713 7001_ $$00000-0002-5515-1821$$aSchade, Dennis$$b19$$eCorresponding author
000619713 773__ $$0PERI:(DE-600)1491411-6$$a10.1021/acs.jmedchem.2c01199$$gVol. 65, no. 22, p. 15263 - 15281$$n22$$p15263 - 15281$$tJournal of medicinal chemistry$$v65$$x0095-9065$$y2022
000619713 8564_ $$uhttps://pubs.acs.org/doi/full/10.1021/acs.jmedchem.2c01199
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