8PUY
TEAD2 with a covalent inhibitor
Summary for 8PUY
| Entry DOI | 10.2210/pdb8puy/pdb |
| Related | 8PUX |
| Descriptor | Transcriptional enhancer factor TEF-4, ~{N}-[3-[(3-pentoxyphenyl)amino]phenyl]propanamide, MYRISTIC ACID, ... (4 entities in total) |
| Functional Keywords | tead2, inhibitor, covalent, signaling protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 55533.00 |
| Authors | Guichou, J.F.,Gelin, M.,Allemand, F. (deposition date: 2023-07-17, release date: 2023-12-13, Last modification date: 2024-11-06) |
| Primary citation | Fnaiche, A.,Chan, H.C.,Paquin, A.,Gonzalez Suarez, N.,Vu, V.,Li, F.,Allali-Hassani, A.,Cao, M.A.,Szewczyk, M.M.,Bolotokova, A.,Allemand, F.,Gelin, M.,Barsyte-Lovejoy, D.,Santhakumar, V.,Vedadi, M.,Guichou, J.F.,Annabi, B.,Gagnon, A. Development of HC-258, a Covalent Acrylamide TEAD Inhibitor That Reduces Gene Expression and Cell Migration. Acs Med.Chem.Lett., 14:1746-1753, 2023 Cited by PubMed Abstract: The transcription factor YAP-TEAD is the downstream effector of the Hippo pathway which controls cell proliferation, apoptosis, tissue repair, and organ growth. Dysregulation of the Hippo pathway has been correlated with carcinogenic processes. A co-crystal structure of TEAD with its endogenous ligand palmitic acid (PA) as well as with flufenamic acid (FA) has been disclosed. Here we report the development of HC-258, which derives from FA and possesses an oxopentyl chain that mimics a molecule of PA as well as an acrylamide that reacts covalently with TEAD's cysteine. HC-258 reduces the , , , and transcript levels and inhibits the migration of MDA-MB-231 breast cancer cells. Co-crystallization with hTEAD2 confirmed that HC-258 binds within TEAD's PA pocket, where it forms a covalent bond with its cysteine. PubMed: 38116405DOI: 10.1021/acsmedchemlett.3c00386 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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