9EWT

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 9EWT

• Entry DOI: 10.2210/pdb9ewt/pdb
• Descriptor: Epidermal growth factor receptor, 1-[2-[3-[(E)-2-(5-cyclopropyl-1,3-oxazol-2-yl)ethenyl]phenyl]-3-pyridin-4-yl-4,6-dihydropyrrolo[3,4-d]imidazol-5-yl]propan-1-one (3 entities in total)
• Functional Keywords: egfr, exon20 insertion, npg, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 76452.23

Authors

Hargreaves, D. (deposition date: 2024-04-04, release date: 2024-10-16)

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

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: 39340451
DOI: 10.1021/acs.jmedchem.4c01792

Experimental method

X-RAY DIFFRACTION (3.019 Å)