Targeted degradation of specific TEAD paralogs by small molecule degraders

Our plain-English summary of Targeted degradation of specific TEAD paralogs by small molecule degraders, by H. Chen, A. Gridnev, N. Schlamowitz, et al (Heliyon, 2024).

The study

• Authors: H. Chen, A. Gridnev, N. Schlamowitz, W. Hu, K. Dey, G. Zheng, J.R. Misra
• Journal: Heliyon
• Published: 2024;10(18):e37829
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The transcription factors, TEAD1-4 together with their co-activator YAP/TAZ function as key downstream effectors of the Hippo pathway. Hyperactivation of TEAD-YAP/TAZ activity is observed in many human cancers. TEAD1-4 possess distinct physiological and pathological functions, with conserved sequences and structures. Targeting specific isoforms within TEAD1-4 can serve as valuable chemical probes for investigating TEAD-related functions in both development and diseases. We report the TEAD-targeting proteolysis targeting chimera (PROTAC), HC278, which achieves effective and specific targeting of TEAD1 and TEAD3 at low nanomolar doses while weakly degrading TEAD2 and TEAD4 at higher doses. Proteomic analysis of >6000 proteins confirmed their highly selective TEAD1 and TEAD3 degradation. Consistently, HC278 can suppress the proliferation of YAP-dependent NCI-H226 mesothelioma cells. Mechanistic exploration revealed that both CRBN and proteasome systems are involved in the TEAD degradation induced by HC278. Moreover, RNA-seq and Gene Set Enrichment Analysis (GSEA) revealed that the YAP signature genes such as CTGF, CYR61, and ANKRD1 are significantly downregulated by HC278 treatment. Overall, HC278 serves as a valuable chemical tool for unraveling the intricate biological roles of TEAD1 and TEAD3 and holds the potential as a lead compound for developing targeted therapy for TEAD1/3-driven pathologies.

© 2024 The Authors.

In plain English

This laboratory study designed, synthesised and tested small-molecule degraders (PROTACs) targeting the Hippo pathway transcription factors TEAD1-4. No asbestos exposure or human participants were involved; the cells were HEK293 engineered to express all four epitope-tagged TEAD paralogs and the mesothelioma lines NCI-H226 (NF2-deleted) and NCI-H28, while the RT-qPCR methods also name MDA-MB-231 cells although the results describe that experiment in NCI-H226 cells. Fourteen compounds were screened and three (HC242, HC278, HC286) were characterised further. All three degraded TEAD1 and TEAD3 even at 50 nM, had little effect on TEAD2 and only weakly degraded TEAD4 at 500 nM. Co-treatment with the proteasome inhibitor MG132, or with the warheads 15 and Ex. 29, inhibited degradation; tested alone, HC278-Neg1 showed a much weaker effect and HC278-Neg2, which cannot engage CRBN, failed to degrade TEAD. In a cell-free assay HC278 formed stable ternary complexes with CRBN/DDB1 and TEAD1 or TEAD3, but only weakly with TEAD2 and TEAD4. Proteomics and RNA-sequencing in NCI-H226 cells showed loss of TEAD1 and TEAD3 and downregulation of YAP target genes CTGF, CYR61 and ANKRD1. HC278 and HC286 reduced NCI-H226 colony formation at 200 nM, with no apparent effect on NCI-H28 cells.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory chemistry and cell-culture study: synthesis and characterisation of small-molecule PROTAC degraders, tested in engineered and cancer cell lines plus a cell-free binding assay
• Who was studied: Cultured human cell lines: HEK293 (including a stable clone expressing epitope-tagged TEAD1-4), NCI-H226 mesothelioma cells and NCI-H28 control mesothelioma cells; no human participants
• Exposure: Treatment of cells with synthesised TEAD-targeting PROTACs, chiefly HC242, HC278 and HC286 (and negative controls HC278-Neg1, HC278-Neg2), at nanomolar concentrations; no asbestos or fibre exposure studied
• Main results:
  • In HEK293 cells expressing tagged TEAD1-4, all three PROTACs degraded TEAD1 and TEAD3 at 50 nM, with little effect on TEAD2 and only weak degradation of TEAD4 at 500 nM
  • Co-treatment with the proteasome inhibitor MG132 completely blocked TEAD degradation by the PROTACs
  • Co-treatment with the warheads 15 and Ex. 29 also inhibited the PROTACs' degradation of TEAD proteins
  • Tested on its own, the negative control HC278-Neg1 (enantiomeric TEAD-binding warhead) produced a much weaker degradative effect
  • Tested on its own, the negative control HC278-Neg2, with a CRBN ligand that cannot engage CRBN, did not induce TEAD degradation
  • In the cell-free AlphaLISA assay, HC278 formed stable ternary complexes with TEAD1 and TEAD3 and CRBN/DDB1, while TEAD2 and TEAD4 formed them only weakly
  • Proteomic profiling of NCI-H226 cells treated with 500 nM HC278 for 24 h showed significant downregulation of TEAD1 and TEAD3; TEAD2 was not detectable in these cells
  • mRNA levels of the YAP target genes CTGF, CYR61 and ANKRD1 were significantly downregulated in HC278-treated NCI-H226 cells compared with DMSO
  • HC278 and HC286 significantly inhibited colony formation by NCI-H226 mesothelioma cells at 200 nM but not at 100 nM, with no apparent effect on NCI-H28 control cells at 200 nM
• The authors' conclusion: The authors concluded that they identified potent and specific PROTAC degraders of TEAD1 and TEAD3 that they consider valuable tools for studying these paralogs
• Limitations the authors state:
  • The authors stated that further work is needed to show whether TEAD degraders are better than autopalmitoylation inhibitors regarding resistance
  • The authors stated that the structural basis of the selective ternary complex formation is not yet established

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Targeted Therapy.

Related studies

• Discovery of a Potent and Selective TEAD Degrader with Durable Degradation Activity — L. Cao, J. Yang, et al. (2025)
• Structure-based discovery of a novel small-molecule inhibitor of TEAD palmitoylation with anticancer activity — A. Gridnev, S. Maity, et al. (2022)
• Experimental assessment of computationally nominated small molecules targeting the YAP-TEAD interface in Hippo pathway-altered mesothelioma cell models — G.J. Weiss, J.C. Loftus, et al. (2026)
• Distribution of 6-6(n)-3[H]sucrose and its radiolabeled degradation products from isolated, perfused rat small intestine loops following prolonged ingestion of chrysotile asbestos — R. Jacobs, R.J. Richards (1980)
• Small-molecule inhibition of oncogenic eukaryotic protein translation in mesothelioma cells — E.Z. Chen, B.A. Jacobson, et al. (2014)
• CARP-1 functional mimetics are a novel class of small molecule inhibitors of malignant pleural mesothelioma cells — S. Jamal, V.T. Cheriyan, et al. (2014)

Browse more research in Heliyon, or return to medical research.