Faculty of Chemistry and Chemical Biology, Technical University Dortmund, Otto-Hahn-Strasse 6, 44227 Dortmund, Germany.
Compound Management and Screening Center, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
J Med Chem. 2022 Mar 10;65(5):3978-3990. doi: 10.1021/acs.jmedchem.1c01800. Epub 2022 Feb 2.
We report on the feasibility to harness embryonic development for the identification of small-molecule cytokine mimetics and signaling activators. Here, a phenotypic, target-agnostic, high-throughput assay is presented that probes bone morphogenetic protein (BMP) signaling during mesodermal patterning of embryonic stem cells. The temporal discrimination of BMP- and transforming growth factor-β (TGFβ)-driven stages of cardiomyogenesis underpins a selective, authentic orchestration of BMP cues that can be recapitulated for the discovery of BMP activator chemotypes. Proof of concept is shown from a chemical screen of 7000 compounds, provides a robust hit validation workflow, and afforded 2,3-disubstituted 4-chromen-4-ones as potent BMP potentiators with osteogenic efficacy. Mechanistic studies suggest that Chromenone enhances canonical BMP outputs at the expense of TGFβ-Smads in an unprecedented manner. Pharmacophoric features were defined, providing a set of novel chemical probes for various applications in (stem) cell biology, regenerative medicine, and basic research on the BMP pathway.
我们报告了利用胚胎发育来鉴定小分子细胞因子模拟物和信号激活剂的可行性。在这里，我们提出了一种表型、无靶点、高通量的测定方法，用于探测胚胎干细胞中中胚层模式形成过程中的骨形态发生蛋白（BMP）信号。BMP 和转化生长因子-β（TGFβ）驱动的心肌发生阶段的时间分辨为 BMP 线索的选择性、真实的编排提供了基础，这种编排可用于发现 BMP 激活剂化学型。从对 7000 种化合物的化学筛选中得到了概念验证，提供了稳健的命中验证工作流程，并获得了 2,3-二取代 4-色满-4-酮作为具有成骨功效的有效 BMP 增强剂。机制研究表明，Chromenone 以一种前所未有的方式以牺牲 TGFβ-Smads 为代价增强了经典的 BMP 输出。定义了药效团特征，为（干细胞）生物学、再生医学和 BMP 途径的基础研究中的各种应用提供了一组新的化学探针。
