Cargando…

Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling

The transcription factor TEAD, together with its coactivator YAP/TAZ, is a key transcriptional modulator of the Hippo pathway. Activation of TEAD transcription by YAP has been implicated in a number of malignancies, and this complex represents a promising target for drug discovery. However, both YAP...

Descripción completa

Detalles Bibliográficos
Autores principales: Fan, Mengyang, Lu, Wenchao, Che, Jianwei, Kwiatkowski, Nicholas P, Gao, Yang, Seo, Hyuk-Soo, Ficarro, Scott B, Gokhale, Prafulla C, Liu, Yao, Geffken, Ezekiel A, Lakhani, Jimit, Song, Kijun, Kuljanin, Miljan, Ji, Wenzhi, Jiang, Jie, He, Zhixiang, Tse, Jason, Boghossian, Andrew S, Rees, Matthew G, Ronan, Melissa M, Roth, Jennifer A, Mancias, Joseph D, Marto, Jarrod A, Dhe-Paganon, Sirano, Zhang, Tinghu, Gray, Nathanael S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9728995/
https://www.ncbi.nlm.nih.gov/pubmed/36300789
http://dx.doi.org/10.7554/eLife.78810
_version_ 1784845394218319872
author Fan, Mengyang
Lu, Wenchao
Che, Jianwei
Kwiatkowski, Nicholas P
Gao, Yang
Seo, Hyuk-Soo
Ficarro, Scott B
Gokhale, Prafulla C
Liu, Yao
Geffken, Ezekiel A
Lakhani, Jimit
Song, Kijun
Kuljanin, Miljan
Ji, Wenzhi
Jiang, Jie
He, Zhixiang
Tse, Jason
Boghossian, Andrew S
Rees, Matthew G
Ronan, Melissa M
Roth, Jennifer A
Mancias, Joseph D
Marto, Jarrod A
Dhe-Paganon, Sirano
Zhang, Tinghu
Gray, Nathanael S
author_facet Fan, Mengyang
Lu, Wenchao
Che, Jianwei
Kwiatkowski, Nicholas P
Gao, Yang
Seo, Hyuk-Soo
Ficarro, Scott B
Gokhale, Prafulla C
Liu, Yao
Geffken, Ezekiel A
Lakhani, Jimit
Song, Kijun
Kuljanin, Miljan
Ji, Wenzhi
Jiang, Jie
He, Zhixiang
Tse, Jason
Boghossian, Andrew S
Rees, Matthew G
Ronan, Melissa M
Roth, Jennifer A
Mancias, Joseph D
Marto, Jarrod A
Dhe-Paganon, Sirano
Zhang, Tinghu
Gray, Nathanael S
author_sort Fan, Mengyang
collection PubMed
description The transcription factor TEAD, together with its coactivator YAP/TAZ, is a key transcriptional modulator of the Hippo pathway. Activation of TEAD transcription by YAP has been implicated in a number of malignancies, and this complex represents a promising target for drug discovery. However, both YAP and its extensive binding interfaces to TEAD have been difficult to address using small molecules, mainly due to a lack of druggable pockets. TEAD is post-translationally modified by palmitoylation that targets a conserved cysteine at a central pocket, which provides an opportunity to develop cysteine-directed covalent small molecules for TEAD inhibition. Here, we employed covalent fragment screening approach followed by structure-based design to develop an irreversible TEAD inhibitor MYF-03–69. Using a range of in vitro and cell-based assays we demonstrated that through a covalent binding with TEAD palmitate pocket, MYF-03–69 disrupts YAP-TEAD association, suppresses TEAD transcriptional activity and inhibits cell growth of Hippo signaling defective malignant pleural mesothelioma (MPM). Further, a cell viability screening with a panel of 903 cancer cell lines indicated a high correlation between TEAD-YAP dependency and the sensitivity to MYF-03–69. Transcription profiling identified the upregulation of proapoptotic BMF gene in cancer cells that are sensitive to TEAD inhibition. Further optimization of MYF-03–69 led to an in vivo compatible compound MYF-03–176, which shows strong antitumor efficacy in MPM mouse xenograft model via oral administration. Taken together, we disclosed a story of the development of covalent TEAD inhibitors and its high therapeutic potential for clinic treatment for the cancers that are driven by TEAD-YAP alteration.
format Online
Article
Text
id pubmed-9728995
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher eLife Sciences Publications, Ltd
record_format MEDLINE/PubMed
spelling pubmed-97289952022-12-08 Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling Fan, Mengyang Lu, Wenchao Che, Jianwei Kwiatkowski, Nicholas P Gao, Yang Seo, Hyuk-Soo Ficarro, Scott B Gokhale, Prafulla C Liu, Yao Geffken, Ezekiel A Lakhani, Jimit Song, Kijun Kuljanin, Miljan Ji, Wenzhi Jiang, Jie He, Zhixiang Tse, Jason Boghossian, Andrew S Rees, Matthew G Ronan, Melissa M Roth, Jennifer A Mancias, Joseph D Marto, Jarrod A Dhe-Paganon, Sirano Zhang, Tinghu Gray, Nathanael S eLife Biochemistry and Chemical Biology The transcription factor TEAD, together with its coactivator YAP/TAZ, is a key transcriptional modulator of the Hippo pathway. Activation of TEAD transcription by YAP has been implicated in a number of malignancies, and this complex represents a promising target for drug discovery. However, both YAP and its extensive binding interfaces to TEAD have been difficult to address using small molecules, mainly due to a lack of druggable pockets. TEAD is post-translationally modified by palmitoylation that targets a conserved cysteine at a central pocket, which provides an opportunity to develop cysteine-directed covalent small molecules for TEAD inhibition. Here, we employed covalent fragment screening approach followed by structure-based design to develop an irreversible TEAD inhibitor MYF-03–69. Using a range of in vitro and cell-based assays we demonstrated that through a covalent binding with TEAD palmitate pocket, MYF-03–69 disrupts YAP-TEAD association, suppresses TEAD transcriptional activity and inhibits cell growth of Hippo signaling defective malignant pleural mesothelioma (MPM). Further, a cell viability screening with a panel of 903 cancer cell lines indicated a high correlation between TEAD-YAP dependency and the sensitivity to MYF-03–69. Transcription profiling identified the upregulation of proapoptotic BMF gene in cancer cells that are sensitive to TEAD inhibition. Further optimization of MYF-03–69 led to an in vivo compatible compound MYF-03–176, which shows strong antitumor efficacy in MPM mouse xenograft model via oral administration. Taken together, we disclosed a story of the development of covalent TEAD inhibitors and its high therapeutic potential for clinic treatment for the cancers that are driven by TEAD-YAP alteration. eLife Sciences Publications, Ltd 2022-10-27 /pmc/articles/PMC9728995/ /pubmed/36300789 http://dx.doi.org/10.7554/eLife.78810 Text en © 2022, Fan, Lu et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry and Chemical Biology
Fan, Mengyang
Lu, Wenchao
Che, Jianwei
Kwiatkowski, Nicholas P
Gao, Yang
Seo, Hyuk-Soo
Ficarro, Scott B
Gokhale, Prafulla C
Liu, Yao
Geffken, Ezekiel A
Lakhani, Jimit
Song, Kijun
Kuljanin, Miljan
Ji, Wenzhi
Jiang, Jie
He, Zhixiang
Tse, Jason
Boghossian, Andrew S
Rees, Matthew G
Ronan, Melissa M
Roth, Jennifer A
Mancias, Joseph D
Marto, Jarrod A
Dhe-Paganon, Sirano
Zhang, Tinghu
Gray, Nathanael S
Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling
title Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling
title_full Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling
title_fullStr Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling
title_full_unstemmed Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling
title_short Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling
title_sort covalent disruptor of yap-tead association suppresses defective hippo signaling
topic Biochemistry and Chemical Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9728995/
https://www.ncbi.nlm.nih.gov/pubmed/36300789
http://dx.doi.org/10.7554/eLife.78810
work_keys_str_mv AT fanmengyang covalentdisruptorofyapteadassociationsuppressesdefectivehipposignaling
AT luwenchao covalentdisruptorofyapteadassociationsuppressesdefectivehipposignaling
AT chejianwei covalentdisruptorofyapteadassociationsuppressesdefectivehipposignaling
AT kwiatkowskinicholasp covalentdisruptorofyapteadassociationsuppressesdefectivehipposignaling
AT gaoyang covalentdisruptorofyapteadassociationsuppressesdefectivehipposignaling
AT seohyuksoo covalentdisruptorofyapteadassociationsuppressesdefectivehipposignaling
AT ficarroscottb covalentdisruptorofyapteadassociationsuppressesdefectivehipposignaling
AT gokhaleprafullac covalentdisruptorofyapteadassociationsuppressesdefectivehipposignaling
AT liuyao covalentdisruptorofyapteadassociationsuppressesdefectivehipposignaling
AT geffkenezekiela covalentdisruptorofyapteadassociationsuppressesdefectivehipposignaling
AT lakhanijimit covalentdisruptorofyapteadassociationsuppressesdefectivehipposignaling
AT songkijun covalentdisruptorofyapteadassociationsuppressesdefectivehipposignaling
AT kuljaninmiljan covalentdisruptorofyapteadassociationsuppressesdefectivehipposignaling
AT jiwenzhi covalentdisruptorofyapteadassociationsuppressesdefectivehipposignaling
AT jiangjie covalentdisruptorofyapteadassociationsuppressesdefectivehipposignaling
AT hezhixiang covalentdisruptorofyapteadassociationsuppressesdefectivehipposignaling
AT tsejason covalentdisruptorofyapteadassociationsuppressesdefectivehipposignaling
AT boghossianandrews covalentdisruptorofyapteadassociationsuppressesdefectivehipposignaling
AT reesmatthewg covalentdisruptorofyapteadassociationsuppressesdefectivehipposignaling
AT ronanmelissam covalentdisruptorofyapteadassociationsuppressesdefectivehipposignaling
AT rothjennifera covalentdisruptorofyapteadassociationsuppressesdefectivehipposignaling
AT manciasjosephd covalentdisruptorofyapteadassociationsuppressesdefectivehipposignaling
AT martojarroda covalentdisruptorofyapteadassociationsuppressesdefectivehipposignaling
AT dhepaganonsirano covalentdisruptorofyapteadassociationsuppressesdefectivehipposignaling
AT zhangtinghu covalentdisruptorofyapteadassociationsuppressesdefectivehipposignaling
AT graynathanaels covalentdisruptorofyapteadassociationsuppressesdefectivehipposignaling