8PO4

Discovery and Optimisation of Potent, Efficacious and Selective Inhibitors Targeting EGFR Exon20 Insertion Mutations. Compound 33 bound to EGFR[V948R]

Summary for 8PO4

• Entry DOI: 10.2210/pdb8po4/pdb
• Descriptor: Epidermal growth factor receptor, 1-cyclopropyl-~{N}-[3-[1-(1-propanoylazetidin-3-yl)-4-pyridin-4-yl-pyrazol-3-yl]phenyl]imidazole-4-carboxamide, ADENOSINE-5'-TRIPHOSPHATE, ... (5 entities in total)
• Functional Keywords: egfr, exon 20 insertion, non-small cell lung cancer, oncology, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 75911.59

Authors

Hargreaves, D. (deposition date: 2023-07-03, release date: 2024-06-05, Last modification date: 2024-06-19)

Primary citation

Thomson, C.,Barton, P.,Braybrooke, E.,Colclough, N.,Dong, Z.,Evans, L.,Floc'h, N.,Guerot, C.,Hargreaves, D.,Khurana, P.,Li, S.,Li, X.,Lister, A.,McCoull, W.,McWilliams, L.,Orme, J.P.,Packer, M.J.,Swaih, A.M.,Ward, R.A.,Winlow, P.,Ye, Y.
Discovery and Optimization of Potent, Efficacious and Selective Inhibitors Targeting EGFR Exon20 Insertion Mutations.
J.Med.Chem., 67:8988-9027, 2024

PubMed Abstract: Herein, we report the identification and optimization of a series of potent inhibitors of EGFR Exon20 insertions with significant selectivity over wild-type EGFR. A strategically designed HTS campaign, multiple iterations of structure-based drug design (SBDD), and tactical linker replacement led to a potent and wild-type selective series of molecules and ultimately the discovery of . Compound is a potent and selective inhibitor of EGFR Exon20 insertions and has demonstrated encouraging efficacy in NSCLC EGFR CRISPR-engineered H2073 xenografts that carry an SVD Exon20 insertion and reduced efficacy in a H2073 wild-type EGFR xenograft model compared to CLN-081 (), indicating that may have lower EGFR wild-type associated toxicity.

PubMed: 38770784
DOI: 10.1021/acs.jmedchem.4c00227

Experimental method

X-RAY DIFFRACTION (1.621 Å)