Molecular Features of the YAP Inhibitor Verteporfin: Synthesis of Hexasubstituted Dipyrrins as Potential Inhibitors of YAP/TAZ, the Downstream Effectors of the Hippo Pathway.
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.
Department of Onco and NeuroChemistry, University of Lille, INSERM UMR-S 1172, Jean-Pierre Aubert Research Center, 3, rue du professeur Laguesse, BP 83, 59006, Lille Cedex, France.
Floriane
F
Gibault
Department of Onco and NeuroChemistry, University of Lille, INSERM UMR-S 1172, Jean-Pierre Aubert Research Center, 3, rue du professeur Laguesse, BP 83, 59006, Lille Cedex, France.
Fabrice
F
Bailly
Department of Mucins, Epithelial Differentiation and Carcinogenesis, University of Lille, INSERM UMR-S 1172, Jean-Pierre Aubert Research Center, Bâtiment Biserte, 1, place de Verdun, 59045, Lille Cedex, France.
Matthieu
M
Corvaisier
Department of Onco and NeuroChemistry, University of Lille, INSERM UMR-S 1172, Jean-Pierre Aubert Research Center, 3, rue du professeur Laguesse, BP 83, 59006, Lille Cedex, France.
Mathilde
M
Coevoet
Department of Mucins, Epithelial Differentiation and Carcinogenesis, University of Lille, INSERM UMR-S 1172, Jean-Pierre Aubert Research Center, Bâtiment Biserte, 1, place de Verdun, 59045, Lille Cedex, France.
Guillemette
G
Huet
Department of Onco and NeuroChemistry, University of Lille, INSERM UMR-S 1172, Jean-Pierre Aubert Research Center, 3, rue du professeur Laguesse, BP 83, 59006, Lille Cedex, France.
Patricia
0000-0002-9555-3446
P
Melnyk
Department of Onco and NeuroChemistry, University of Lille, INSERM UMR-S 1172, Jean-Pierre Aubert Research Center, 3, rue du professeur Laguesse, BP 83, 59006, Lille Cedex, France.
Philippe
0000-0003-0924-0433
P
Cotelle
D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D000090683:Hippo Signaling Pathway; D006801:Humans; D015394:Molecular Structure; D010750:Phosphoproteins / Q000037:antagonists & inhibitors*; D017319:Photosensitizing Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011166:Porphyrins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D000077362:Verteporfin; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D017319:Photosensitizing Agents; D011166:Porphyrins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D000077362:Verteporfin; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; D017346:Protein Serine-Threonine Kinases
Hippo pathway; cancer; dipyrrins; non-photoinduced therapy; verteporfin