Exploring structural and biological insights of TEAD through rational design and synthesis of niflumic acid derivatives

Our plain-English summary of Exploring structural and biological insights of TEAD through rational design and synthesis of niflumic acid derivatives, by Y.S. Choi, Y.J. Kim, Y. Jeon, et al (Journal of Enzyme Inhibition and Medicinal Chemistry, 2024).

The study

• Authors: Y.S. Choi, Y.J. Kim, Y. Jeon, J.S. Kang, J. Lee, E. Hong, Y.H. Park, W. Kim, B. Cha, R. Jeon
• Journal: Journal of Enzyme Inhibition and Medicinal Chemistry
• Published: 2024;39(1):2419925
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Transcriptional enhanced associate domain (TEAD) transcription factors undergo auto-palmitoylation, which is critical to mediate their function and maintain stability. Targeting the palmitate binding pocket of TEAD holds considerable promise for drug discovery, and it can be characterised into three components: a conserved cysteine, a hydrophobic main pocket, and a hydrophilic side pocket. Endogenous palmitate and several known TEAD inhibitors interact with the cysteine and hydrophobic residues in the deep hydrophobic pocket. We anticipate that precise targeting of the polar side pocket could facilitate the discovery of inhibitors with enhanced potencies and properties. Herein, we selected niflumic acid as the core scaffold suitable for targeting the three characteristic components of TEAD palmitate pocket. Reversible and irreversible compounds with substituents capable of directing each part of the palmitate pocket were designed. The newly synthesised compounds inhibited the palmitoylation and transcriptional activity of TEAD and elicited growth-inhibitory effects against several carcinomas, including mesothelioma.

In plain English

This was a laboratory chemistry and cell-based study, not a study of people or asbestos exposure. The authors designed and synthesised a series of niflumic acid (and one flufenamic acid) derivatives intended to reach three parts of the palmitate binding pocket of TEAD transcription factors: a conserved cysteine, a hydrophobic main pocket and a hydrophilic side pocket. Compounds were tested in a TEAD luciferase reporter assay, a thiol conjugation assay, a TEAD palmitoylation inhibition assay, computer docking against a TEAD2 crystal structure, and growth inhibition assays in cancer cell lines. In the thiol conjugation assay compounds 5a, 5b and 5k gave IC50 values of 5.82, 1.04 and 0.32 micromolar, compared with 29.87 micromolar for niflumic acid itself. The same three compounds inhibited TEAD4 palmitoylation with IC50 values of 0.97, 0.81 and 0.40 micromolar. In the mesothelioma line NCI-H226 the GI50 values were 29.07, 16.18 and 12.85 micromolar for 5a, 5b and 5k, while niflumic acid and flufenamic acid were above 40 micromolar.

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 study: rational design, chemical synthesis, molecular docking and in vitro biochemical and cell assays of TEAD inhibitors
• Who was studied: Not human subjects: recombinant His6-tagged TEAD4 protein, a TEAD reporter MCF7 recombinant cell line, HEK293A-LATS1/2 double knockout cells, and cancer cell lines including the mesothelioma lines NCI-H226 and NCI-H28, plus HCT-116, NCI-H23, MDA-MB-231, HCT-15, BXPC-3, PC-3 and U-87MG
• Exposure: Treatment of proteins and cells with synthesised niflumic acid and flufenamic acid derivatives (reversible compounds 3a, 3b, 6a and acryloyl 'irreversible' compounds 5a-5k) and the reference inhibitor TED-347, at stated concentrations
• Main results:
  • In the TEAD reporter assay at 100 micromolar, activity remaining was 5.4 ± 0.6% for 5a and 1.6 ± 0.1% for 5b, while niflumic acid (3a) showed no inhibition (172.3 ± 5.5%)
  • Thiol conjugation assay IC50 values: 5a 5.82, 5b 1.04, 5k 0.32 micromolar; niflumic acid (3a) 29.87 micromolar
  • TEAD4 palmitoylation inhibition IC50 values: 5a 0.97, 5b 0.81, 5k 0.40 micromolar; for TEAD1-3, 5b gave 3.38, 1.37 and 0.35 micromolar and 5k gave 1.12, 0.95 and 0.05 micromolar
  • In HEK293A-LATS1/2 double knockout cells (Hippo inactive model) the TEAD reporter IC50 values were 126.77 micromolar for 5a, 35.89 for 5b and 60.81 for 5k
  • Growth inhibition (GI50) in mesothelioma lines: NCI-H226, 5a 29.07, 5b 16.18, 5k 12.85, TED-347 5.09 micromolar; NCI-H28, 5a 5.11, 5b not determined, 5k 11.21, TED-347 1.91 micromolar; flufenamic acid and niflumic acid greater than 40 micromolar in both
  • Docking scores (LF ΔG) were lower (more negative) for the acryloyl compounds than for the reversible compounds, for example −8.309 for 5b versus −6.353 for niflumic acid
• The authors' conclusion: The authors concluded that compounds 5a, 5b and 5k inhibited TEAD palmitoylation and transcription and showed anti-cancer activity against mesothelioma and other cancer cell lines, and that a molecular expanding strategy targeting the hydrophilic side pocket together with the conserved cysteine and hydrophobic main pocket could help identify TEAD inhibitors with enhanced potencies and properties
• Limitations the authors state:
  • The authors state the compounds they made were not the most potent TEAD inhibitors
  • The authors note that adding a long alkyl chain, although improving inhibition, may not be advantageous for compound properties
  • The authors note that in their reporter system niflumic acid showed no inhibitory effect, unlike previous reports at 150 micromolar
  • The authors state that protein-based palmitoylation or TEAD-YAP interaction assays do not directly translate into TEAD-YAP transcriptional activity

Topics

Medical terms in this study, explained in our Lexicon: Discovery, Carcinoma, Mesothelioma.

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