9GC4
Highly optimized CNS penetrant inhibitors of EGFR Exon20 Insertion Mutations
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Summary for 9GC4
| Entry DOI | 10.2210/pdb9gc4/pdb |
| Descriptor | Epidermal growth factor receptor, 1-[2-[3-(3-chloranyl-6-fluoranyl-pyridin-2-yl)oxyphenyl]-3-pyrimidin-4-yl-4,6-dihydropyrrolo[3,4-d]imidazol-5-yl]propan-1-one (3 entities in total) |
| Functional Keywords | egfr, exon20, npg, signaling protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 3 |
| Total formula weight | 114253.54 |
| Authors | Hargreaves, D. (deposition date: 2024-08-01, release date: 2025-02-12, Last modification date: 2025-02-26) |
| Primary citation | McCoull, W.,Thomson, C.,Braybrooke, E.,Chan, C.,Colclough, N.,Cortes Gonzalez, M.A.,Cosulich, S.,Davies, N.L.,Floc'h, N.,Greenwood, R.,Hargreaves, D.,Huang, P.,Hunt, T.A.,Johnson, T.,Johnstrom, P.,Kettle, J.G.,Kondrashov, M.,Kostomiris, D.H.,Li, S.,Lister, A.,Martin, S.,McKerrecher, D.,McLean, N.,Nissink, J.W.M.,Orme, J.P.,Orwig, P.,Packer, M.J.,Pearson, S.,Qin, L.,Felisberto-Rodrigues, C.,Savoca, A.,Schou, M.,Stokes, S.,Swaih, A.M.,Talbot, S.,Tucker, M.J.,Ward, R.A.,Wadforth, E.,Wang, C.,Wilson, J.,Yang, Y. Highly Optimized CNS Penetrant Inhibitors of EGFR Exon20 Insertion Mutations. J.Med.Chem., 68:3700-3748, 2025 Cited by PubMed Abstract: Despite recent advances in the inhibition of EGFR (epidermal growth factor receptor), there remains a clinical need for new EGFR Exon20 insertion (Ex20Ins) inhibitors that spare EGFR WT. Herein, we report the discovery and optimization of two chemical series leading to ether and biaryl as potent, selective, and brain-penetrant inhibitors of Ex20Ins mutants. Building on our earlier discovery of alkyne which allowed access to CNS property space for an Ex20Ins inhibitor, we utilized structure-based design to move to lower lipophilicity and lower CL compounds while maintaining a WT selectivity margin. During optimization, aldehyde oxidase (AO) metabolism was identified as a human clearance risk, and through SAR exploration, lower AO metabolism was achieved. Potency and WT margin were optimized across a range of Ex20Ins mutants including the potential acquired resistance T790M mutant and efficacy demonstrated in an LXF2478 Ex20Ins ASV model with margin to EGFR WT in vivo. PubMed: 39869768DOI: 10.1021/acs.jmedchem.4c02811 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.415 Å) |
Structure validation
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