Wesseler, Fabian, Lohmann, Stefan, Riege, Daniel, Halver, Jonas, Roth, Aileen, Pichlo, Christian, Weber, Sabrina, Takamiya, Masanari ORCID: 0000-0002-6524-5813, Mueller, Eva, Ketzel, Jana, Flegel, Jana, Gihring, Adrian, Rastegar, Sepand ORCID: 0000-0003-4411-5646, Bertrand, Jessica, Baumann, Ulrich, Knippschild, Uwe, Peifer, Christian, Sievers, Sonja, Waldmann, Herbert and Schade, Dennis ORCID: 0000-0002-5515-1821 . Phenotypic Discovery of Triazolo[1,5-c]quinazolines as a First-In- Class Bone Morphogenetic Protein Amplifier Chemotype. J. Med. Chem.. WASHINGTON: AMER CHEMICAL SOC. ISSN 1520-4804

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Wesseler, FabianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lohmann, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riege, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Halver, JonasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roth, AileenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pichlo, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weber, SabrinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Takamiya, MasanariUNSPECIFIEDorcid.org/0000-0002-6524-5813UNSPECIFIED
Mueller, EvaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ketzel, JanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Flegel, JanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gihring, AdrianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rastegar, SepandUNSPECIFIEDorcid.org/0000-0003-4411-5646UNSPECIFIED
Bertrand, JessicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baumann, UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knippschild, UweUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peifer, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sievers, SonjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Waldmann, HerbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schade, DennisUNSPECIFIEDorcid.org/0000-0002-5515-1821UNSPECIFIED
URN: urn:nbn:de:hbz:38-690649
DOI: 10.1021/acs.jmedchem.2c01199
Journal or Publication Title: J. Med. Chem.
Publisher: AMER CHEMICAL SOC
Place of Publication: WASHINGTON
ISSN: 1520-4804
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
TRIAZOLOQUINAZOLINE ADENOSINE ANTAGONIST; ID GENES; INHIBITION; SERIES; ASSAY; SMADMultiple languages
Chemistry, MedicinalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69064

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