Small-Molecule-Mediated Suppression of BMP Signaling by Selective Inhibition of BMP1-Dependent Chordin Cleavage
Autor: | Takamasa Mizoguchi, Shohei Mikami, Mari Yatou, Yui Kondo, Shuhei Omaru, Shuhei Kuwabara, Wataru Okura, Syouta Noda, Takeshi Tenno, Hidekazu Hiroaki, Motoyuki Itoh |
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Jazyk: | angličtina |
Rok vydání: | 2023 |
Předmět: | |
Zdroj: | International Journal of Molecular Sciences, Vol 24, Iss 5, p 4313 (2023) |
Druh dokumentu: | article |
ISSN: | 24054313 1422-0067 1661-6596 |
DOI: | 10.3390/ijms24054313 |
Popis: | BMP signaling is critical for many biological processes. Therefore, small molecules that modulate BMP signaling are useful for elucidating the function of BMP signaling and treating BMP signaling-related diseases. Here, we performed a phenotypic screening in zebrafish to examine the in vivo effects of N-substituted-2-amino-benzoic acid analogs NPL1010 and NPL3008 and found that they affect BMP signaling-dependent dorsal–ventral (D–V) patterning and bone formation in zebrafish embryos. Furthermore, NPL1010 and NPL3008 suppressed BMP signaling upstream of BMP receptors. BMP1 cleaves Chordin, an antagonist of BMP, and negatively regulates BMP signaling. Docking simulations demonstrated that NPL1010 and NPL3008 bind BMP1. We found that NPL1010 and NPL3008 partially rescued the disruptions in the D–V phenotype caused by bmp1 overexpression and selectively inhibited BMP1-dependent Chordin cleavage. Therefore, NPL1010 and NPL3008 are potentially valuable inhibitors of BMP signaling that act through selective inhibition of Chordin cleavage. |
Databáze: | Directory of Open Access Journals |
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