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

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Phenotypic Discovery of Triazolo[1,5-c]quinazolines as a First-In-Class Bone Morphogenetic Protein Amplifier Chemotype
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-11-08 , DOI: 10.1021/acs.jmedchem.2c01199
Fabian Wesseler _{1,

2,

3} , Stefan Lohmann ₃ , Daniel Riege ₃ , Jonas Halver ₁ , Aileen Roth ₄ , Christian Pichlo ₅ , Sabrina Weber ₆ , Masanari Takamiya ₆ , Eva Müller ₇ , Jana Ketzel ₃ , Jana Flegel ₁ , Adrian Gihring ₄ , Sepand Rastegar ₆ , Jessica Bertrand ₇ , Ulrich Baumann ₅ , Uwe Knippschild ₄ , Christian Peifer ₃ , Sonja Sievers _{2,

8} , Herbert Waldmann _{1,

8} , Dennis Schade _{3,

9}

Affiliation

Faculty of Chemistry and Chemical Biology, Technical University Dortmund, Otto-Hahn-Strasse 6, 44227Dortmund, Germany.
Compound Management and Screening Center COMAS, Max Planck Institute of Molecular Physiology (MPI), 44227Dortmund, Germany.
Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Christian-Albrechts University of Kiel, Gutenbergstrasse 76, 24118Kiel, Germany.
Department of General and Visceral Surgery, University Hospital Ulm, Albert-Einstein-Allee 23, 89081Ulm, Germany.
Department of Chemistry, University of Cologne, Greinstraße 6, 50939Cologne, Germany.
Institute of Biological and Chemical Systems - Biological Information Processing at Karlsruhe Institute of Technology (KIT), 76344Eggenstein-Leopoldshafen, Germany.
Department of Orthopedic Surgery, Otto-von-Guericke University, 39120Magdeburg, Germany.
Max-Planck-Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227Dortmund, Germany.
Partner Site Kiel, DZHK, German Center for Cardiovascular Research, 24105Kiel, Germany.

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.

中文翻译：

三唑并 [1,5-c] 喹唑啉作为一流骨形态发生蛋白放大器化学型的表型发现

表型药物发现 (PDD) 继续以一流的治疗方式推动研发管道，但成功率主要取决于基础模型系统的质量。在这里，我们采用了一种基于干细胞的方法来发现与目标无关但以通路为中心的小分子细胞因子信号激活剂，以在发育和再生过程中充当形态发生素。公正筛选鉴定出三唑并 [1,5- c]喹唑啉作为骨形态发生蛋白 (BMP) 通路的体外和体内活性放大器。细胞 BMP 输出通过 BMP-Smad 蛋白的增强和持续可用性来刺激，严格依赖于最小的 BMP 输入。整体目标反卷积揭示了一种独特的双重靶向机制，即酪蛋白激酶 1 和磷脂酰肌醇 3-激酶同种型作为有效放大成骨 BMP 信号传导的关键效应物。这项工作强调了 PDD 发现未被识别的多药理学特征的资产，在这种情况下显着扩展了 BMP 调制器的化学和药物空间。

更新日期：2022-11-08

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