Protein-Protein Interaction Disruptors of the YAP/TAZ-TEAD Transcriptional Complex
The identification of protein-protein interaction disruptors (PPIDs) that disrupt the YAP/TAZ-TEAD interaction has gained considerable momentum. Several studies have shown that YAP/TAZ are no longer oncogenic when their interaction with the TEAD family of transcription factors is disrupted. The tran...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-12-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/24/6001 |
| _version_ | 1797544254817435648 |
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| author | Ajaybabu V. Pobbati Brian P. Rubin |
| author_facet | Ajaybabu V. Pobbati Brian P. Rubin |
| author_sort | Ajaybabu V. Pobbati |
| collection | DOAJ |
| description | The identification of protein-protein interaction disruptors (PPIDs) that disrupt the YAP/TAZ-TEAD interaction has gained considerable momentum. Several studies have shown that YAP/TAZ are no longer oncogenic when their interaction with the TEAD family of transcription factors is disrupted. The transcriptional co-regulator YAP (its homolog TAZ) interact with the surface pockets of TEADs. Peptidomimetic modalities like cystine-dense peptides and YAP cyclic and linear peptides exploit surface pockets (interface 2 and interface 3) on TEADs and function as PPIDs. The TEAD surface might pose a challenge for generating an effective small molecule PPID. Interestingly, TEADs also have a central pocket that is distinct from the surface pockets, and which small molecules leverage exclusively to disrupt the YAP/TAZ-TEAD interaction (allosteric PPIDs). Although small molecules that occupy the central pocket belong to diverse classes, they display certain common features. They are flexible, which allows them to adopt a palmitate-like conformation, and they have a predominant hydrophobic portion that contacts several hydrophobic residues and a small hydrophilic portion that faces the central pocket opening. Despite such progress, more selective PPIDs that also display favorable pharmacokinetic properties and show tolerable toxicity profiles are required to evaluate the feasibility of using these PPIDs for cancer therapy. |
| first_indexed | 2024-03-10T13:56:58Z |
| format | Article |
| id | doaj.art-3ebaf70674fd45b781d076e327fb3536 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T13:56:58Z |
| publishDate | 2020-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-3ebaf70674fd45b781d076e327fb35362023-11-21T01:28:26ZengMDPI AGMolecules1420-30492020-12-012524600110.3390/molecules25246001Protein-Protein Interaction Disruptors of the YAP/TAZ-TEAD Transcriptional ComplexAjaybabu V. Pobbati0Brian P. Rubin1Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USADepartment of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USAThe identification of protein-protein interaction disruptors (PPIDs) that disrupt the YAP/TAZ-TEAD interaction has gained considerable momentum. Several studies have shown that YAP/TAZ are no longer oncogenic when their interaction with the TEAD family of transcription factors is disrupted. The transcriptional co-regulator YAP (its homolog TAZ) interact with the surface pockets of TEADs. Peptidomimetic modalities like cystine-dense peptides and YAP cyclic and linear peptides exploit surface pockets (interface 2 and interface 3) on TEADs and function as PPIDs. The TEAD surface might pose a challenge for generating an effective small molecule PPID. Interestingly, TEADs also have a central pocket that is distinct from the surface pockets, and which small molecules leverage exclusively to disrupt the YAP/TAZ-TEAD interaction (allosteric PPIDs). Although small molecules that occupy the central pocket belong to diverse classes, they display certain common features. They are flexible, which allows them to adopt a palmitate-like conformation, and they have a predominant hydrophobic portion that contacts several hydrophobic residues and a small hydrophilic portion that faces the central pocket opening. Despite such progress, more selective PPIDs that also display favorable pharmacokinetic properties and show tolerable toxicity profiles are required to evaluate the feasibility of using these PPIDs for cancer therapy.https://www.mdpi.com/1420-3049/25/24/6001TEADYAPTAZprotein-protein interaction disruptorsPPIDHippo pathway |
| spellingShingle | Ajaybabu V. Pobbati Brian P. Rubin Protein-Protein Interaction Disruptors of the YAP/TAZ-TEAD Transcriptional Complex Molecules TEAD YAP TAZ protein-protein interaction disruptors PPID Hippo pathway |
| title | Protein-Protein Interaction Disruptors of the YAP/TAZ-TEAD Transcriptional Complex |
| title_full | Protein-Protein Interaction Disruptors of the YAP/TAZ-TEAD Transcriptional Complex |
| title_fullStr | Protein-Protein Interaction Disruptors of the YAP/TAZ-TEAD Transcriptional Complex |
| title_full_unstemmed | Protein-Protein Interaction Disruptors of the YAP/TAZ-TEAD Transcriptional Complex |
| title_short | Protein-Protein Interaction Disruptors of the YAP/TAZ-TEAD Transcriptional Complex |
| title_sort | protein protein interaction disruptors of the yap taz tead transcriptional complex |
| topic | TEAD YAP TAZ protein-protein interaction disruptors PPID Hippo pathway |
| url | https://www.mdpi.com/1420-3049/25/24/6001 |
| work_keys_str_mv | AT ajaybabuvpobbati proteinproteininteractiondisruptorsoftheyaptazteadtranscriptionalcomplex AT brianprubin proteinproteininteractiondisruptorsoftheyaptazteadtranscriptionalcomplex |