8EME

EGFR(T790M/V948R) in complex with ZNL-0056

Summary for 8EME

• Entry DOI: 10.2210/pdb8eme/pdb
• Descriptor: Epidermal growth factor receptor, N-{7-methyl-1-[(3S)-1-(prop-2-enoyl)azepan-3-yl]-1H-benzimidazol-2-yl}-5-(prop-2-enamido)thiophene-3-carboxamide (2 entities in total)
• Functional Keywords: egfr, kinase, covalent, inhibitor, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 75926.77

Authors

Beyett, T.S.,Eck, M.J. (deposition date: 2022-09-27, release date: 2023-10-18, Last modification date: 2024-11-13)

Primary citation

Li, Z.,Jiang, J.,Ficarro, S.B.,Beyett, T.S.,To, C.,Tavares, I.,Zhu, Y.,Li, J.,Eck, M.J.,Janne, P.A.,Marto, J.A.,Zhang, T.,Che, J.,Gray, N.S.
Molecular Bidents with Two Electrophilic Warheads as a New Pharmacological Modality.
Acs Cent.Sci., 10:1156-1166, 2024

PubMed Abstract: A systematic strategy to develop dual-warhead inhibitors is introduced to circumvent the limitations of conventional covalent inhibitors such as vulnerability to mutations of the corresponding nucleophilic residue. Currently, all FDA-approved covalent small molecules feature one electrophile, leaving open a facile route to acquired resistance. We conducted a systematic analysis of human proteins in the protein data bank to reveal ∼400 unique targets amendable to dual covalent inhibitors, which we term "molecular bidents". We demonstrated this strategy by targeting two kinases: MKK7 and EGFR. The designed compounds, ZNL-8162 and ZNL-0056, are ATP-competitive inhibitors that form two covalent bonds with cysteines and retain potency against single cysteine mutants. Therefore, molecular bidents represent a new pharmacological modality with the potential for improved selectivity, potency, and drug resistance profile.

PubMed: 38947214
DOI: 10.1021/acscentsci.3c01245

Experimental method

X-RAY DIFFRACTION (3.32 Å)