9EWS
Optimisation of Potent, Efficacious, Selective and Blood-Brain Barrier Penetrating Inhibitors Targeting EGFR Exon20 Insertion Mutations
This is a non-PDB format compatible entry.
Summary for 9EWS
| Entry DOI | 10.2210/pdb9ews/pdb |
| Descriptor | Epidermal growth factor receptor, 1-[3-pyridin-4-yl-2-[3-(2-pyrimidin-2-ylethynyl)phenyl]-4,6-dihydropyrrolo[3,4-d]imidazol-5-yl]propan-1-one, IODIDE ION, ... (4 entities in total) |
| Functional Keywords | egfr, exon20 insertion, npg, signaling protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 40098.62 |
| Authors | |
| Primary citation | Thomson, C.,Braybrooke, E.,Colclough, N.,Davies, N.L.,Floc'h, N.,Greenwood, R.,Guerot, C.,Hargreaves, D.,Johnstrom, P.,Khurana, P.,Kostomiris, D.H.,Li, S.,Lister, A.,Lorthioir, O.,Martin, S.,McCoull, W.,McLean, N.J.,McWilliams, L.,Orme, J.P.,Packer, M.J.,Pearson, S.,Swaih, A.M.,Tentarelli, S.,Tucker, M.J.,Ward, R.A.,Wilkinson, S.,Winlow, P.,Wood, I.L. Optimization of Potent, Efficacious, Selective and Blood-Brain Barrier Penetrating Inhibitors Targeting EGFR Exon20 Insertion Mutations. J.Med.Chem., 2024 Cited by PubMed Abstract: Herein, we report the optimization of a series of epidermal growth factor receptor (EGFR) Exon20 insertion (Ex20Ins) inhibitors using structure-based drug design (SBDD), leading to the discovery of compound , a potent and wild type selective molecule, which demonstrates efficacy in multiple EGFR Ex20Ins xenograft models and blood-brain barrier penetration in preclinical species. Building on our earlier discovery of an probe, SBDD was used to design a novel bicyclic core with a lower molecular weight to facilitate blood-brain barrier penetration. Further optimization including strategic linker replacement and diversification of the ring system interacting with the c-helix enabled photolytic and metabolic stability improvements. Together with refinement of molecular properties important for achieving high brain exposure, including molecular weight, H-bonding, and polarity, was identified. PubMed: 39340451DOI: 10.1021/acs.jmedchem.4c01792 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.435 Å) |
Structure validation
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