TABLE 3.
YAP/TAZ‐TEAD inhibitors of protein–protein interaction, central pocket binding
| Molecule | Other name(s) | Inhibitory action | Binding validation | Activity validation | Interface | Binding affinity (KD) | IC50 | Reference(s) | Vendor |
|---|---|---|---|---|---|---|---|---|---|
| Flufenamic acid |
Paraflu, Parlef, Ristogen, Sastridex, Tecramine |
API | Co‐crystal structure, molecular modelling, STD NMR | ITC, TEAD luciferase reporter | Central pocket & interface 3 (weak affinity) | 73 μM | NR | 209 |
Tocris (#4522) Merck (#151300) |
| Niflumic acid |
Donalgin, Niflam, Forenol |
API | Co‐crystal structure, molecular modelling, STD NMR | ITC, TEAD luciferase reporter | Central pocket & interface 3 (weak affinity) | 28 μM | NR | 209 |
Tocris (#4112) Merck (#N0630) |
| TED‐347 (compound 2) | API—covalent | Co‐crystal structure, molecular docking, molecular dynamics simulation, protein mass spectrometry, FP |
FP, Biolayer interferometry, Co‐IP, TEAD luciferase reporter, YAP‐TEAD target gene qPCR |
Central pocket | NR | 5.9 μM | 250 |
Selleckchem (#S8951) MedChemExpress (#HY‐125269) |
|
| MYF‐01‐037 | API –covalent | Molecular docking | YAP‐TEAD split Gaussia luciferase assay, YAP‐TEAD target gene qPCR | Central pocket | NR | 0.8 μM | 251 |
Selleckchem (#S8950) Cambridge Bioscience (#B3298‐5) |
|
| Non‐fused tricyclic compound 42 | NR | NR | TEAD luciferase reporter | Central pocket | NR | <0.1 μM | 252 | Patented: WO2018204532A1 | |
| MGH‐CP1 | API | Co‐crystal structure | Co‐IP, TEAD luciferase reporter | Central pocket | NR | 672–710 nM (TEAD isoform‐dependent) | 253 |
Selleckchem (#S9735) |
|
| Indole incorporated triazine derivatives (e.g compound 9) | API | Molecular docking, NanoDSF, FP | NanoDSF, FP, YAP‐TEAD target gene qPCR | Central pocket | NR | 6.75 μM | 254 | ||
| Dihydropyrazolo pyramidines (e.g. compound 7) | NR | NR | TR‐FRET | Central pocket | NR | 18–87 nM (TEAD isoform‐dependent) | 255 | Patented: WO2019232216A1 | |
| K‐975 | K975 | API | Co‐crystal structure, SPR | SPR, pull down assay, YAP‐TEAD target gene qPCR | Central pocket | NR | NR | 256 |
MedChemExpress (#HY‐138565) |
| Kojic acid‐derived Betti bases (e.g. compound 19) | API | FP, whole‐protein ESI–MS spectrometry, NMR | Thiol conjugation assay, FP, cellular thermal shift assay | Central pocket | 28 nM | 0.2 ± 0.04 μM | 257 | ||
| Compound 2 | API | Co‐crystal structure, FP, SPR | FP, TR‐FRET, Co‐IP, SPR | Central pocket | 229 nM | 31.8 nM | 258 | ||
| DC‐TEADin02 | DCTEADin02 | API—covalent | Molecular docking, NMR, SPR, mass spectrometry | Pull‐down assay, TEAD luciferase reporter, YAP‐TEAD target gene qPCR | Central pocket | NR | 197 ± 19 nM | 259 |
MedKoo (#463183) |
| Quinolinol Q2 | API | Molecular docking, molecular dynamics simulation | TEAD luciferase reporter, RNA‐seq | Central pocket | 2.6 ± 0.3 μM | 2.6 μM | 260 |
Hit2Lead (#5926377) Mcule (#MCULE‐5191032439) MolPort (#MolPort‐003‐183‐526) |
Abbreviations: API, autopalmitoylation inhibitor; Co‐IP, co‐immunoprecipitation; ESI‐MS, electrospray ionization mass spectrometry; FP, fluorescence polarization; ITC, isothermal titration calorimetry; MST, microscale thermophoresis; NMR, nuclear magnetic resonance; Nano‐DSF, nano differential scanning fluorimetry; NR, not reported; PLA, proximity ligation assay; SPR, surface plasmon resonance; STD NMR, saturation transfer difference nuclear magnetic resonance; TR‐FRET, time‐resolved fluorescence resonance energy transfer; TSA, thermal shift assay.