9MST

Befotertinib in complex with WT EGFR

This is a non-PDB format compatible entry.

Summary for 9MST

• Entry DOI: 10.2210/pdb9mst/pdb
• Descriptor: Epidermal growth factor receptor, Befotertinib, bound form (3 entities in total)
• Functional Keywords: cancer, drug development, drug resistance, signaling, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 37873.75

Authors

Damghani, T.,Ouellette, E.A.,Heppner, D.E. (deposition date: 2025-01-10, release date: 2025-10-08)

Primary citation

Damghani, T.,Chitnis, S.P.,Abidakun, O.A.,Patel, K.B.,Lin, K.S.,Ouellette, E.A.,Lantry, A.M.,Heppner, D.E.
Profiling and Optimizing Targeted Covalent Inhibitors through EGFR-Guided Studies.
J.Med.Chem., 68:17917-17932, 2025

PubMed Abstract: Targeted covalent inhibitors (TCIs) are actively pursued in drug discovery due to their prolonged target engagement and clinical efficacy. Although kinetic parameters provide a path to their optimization, systematic design strategies and practical guidance remain underexplored. In this study, the EGFR kinase is deployed as a model system to elucidate structural and functional determinants critical for directing the optimization of irreversible TCIs. Functional analyses reveal a two-phase optimization process, underscoring the importance of balancing─rather than maximizing─the inactivation efficiency rate (/). Selective inhibition of the oncogenic L858R/T790M mutant over the wild-type is achieved by tuning this balance, particularly for TCIs exhibiting the fastest /. Structural studies indicate that certain hydrophobic and hydrophilic interactions are associated with L858R/T790M selectivity, offering insights into structure-guided design. These results offer a broadly applicable approach for prioritizing compounds and support the integration of kinetic and selectivity data in TCI discovery campaigns.

PubMed: 40801664
DOI: 10.1021/acs.jmedchem.5c01661

Experimental method

X-RAY DIFFRACTION (2.57 Å)