Summary for 9OS6
| Entry DOI | 10.2210/pdb9os6/pdb |
| Descriptor | Epidermal growth factor receptor, N-{4-(3-chloro-4-fluoroanilino)-7-[3-(morpholin-4-yl)propoxy]quinazolin-6-yl}prop-2-enamide (3 entities in total) |
| Functional Keywords | cancer, drug discovery, covalent, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 37790.07 |
| Authors | |
| 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 Cited by 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: 40801664DOI: 10.1021/acs.jmedchem.5c01661 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.75 Å) |
Structure validation
Download full validation report
