| Title: |
Molecular Features of the YAP Inhibitor Verteporfin: Synthesis of Hexasubstituted Dipyrrins as Potential Inhibitors of YAP/TAZ, the Downstream Effectors of the Hippo Pathway |
| Authors: |
Gibault, Floriane; Bailly, Fabrice; Corvaisier, Mathieu; Coevoet, Mathilde; Huet, Guillemette; Melnyk, Patricia; Cotelle, Philippe |
| Contributors: |
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc); Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille |
| Source: |
ISSN: 1860-7179. |
| Publisher Information: |
CCSD; Wiley-VCH Verlag |
| Publication Year: |
2017 |
| Collection: |
LillOA (HAL Lille Open Archive, Université de Lille) |
| Subject Terms: |
[CHIM.THER]Chemical Sciences/Medicinal Chemistry; [CHIM.ORGA]Chemical Sciences/Organic chemistry; [SDV.CAN]Life Sciences [q-bio]/Cancer |
| Description: |
International audience ; Porphyrin derivatives, in particular verteporfin (VP), a photosensitizer initially designed for cancer therapy, have been identified as inhibitors of the YAP–TEAD interaction and transcriptional activity. Herein we report the efficient convergent synthesis of the dipyrrin half of protoporphyrin IX dimethyl ester (PPIX‐DME), in which the sensitive vinyl group was created at the final stage by a dehydroiodination reaction. Two other dipyrrin derivatives were synthesized, including dipyrrin 19 [(Z)‐2‐((3,5‐dimethyl‐4‐vinyl‐2H‐pyrrol‐2‐ylidene)methyl)‐3,5‐dimethyl‐4‐vinyl‐1H‐pyrrole], containing two vinyl groups. We found that VP and dipyrrin 19 showed significant inhibitory effects on TEAD transcriptional activity in MDA‐MB‐231 human breast cancer cells, whereas other compounds did not show significant changes. In addition, we observed a marked decrease in both YAP and TAZ levels following VP treatment, whereas dipyrrin 19 treatment primarily decreased the levels of YAP and receptor kinase AXL, a downstream target of YAP. Together, our data suggest that, due to their chemical structures, porphyrin‐ and dipyrrin‐related derivatives can directly target YAP and/or TAZ proteins and inhibit TEAD transcriptional activity. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1002/cmdc.201700063 |
| Availability: |
https://hal.science/hal-02060557; https://hal.science/hal-02060557v1/document; https://hal.science/hal-02060557v1/file/10.1002cmdc.201700063%20HAL.pdf; https://doi.org/10.1002/cmdc.201700063 |
| Rights: |
info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.C86997C3 |
| Database: |
BASE |