8F1H

EGFR kinase in complex with TAS6417 (CLN-081)

Summary for 8F1H

• Entry DOI: 10.2210/pdb8f1h/pdb
• Descriptor: Epidermal growth factor receptor, N-[(5P,8S,10R)-4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl]prop-2-enamide, CITRIC ACID, ... (4 entities in total)
• Functional Keywords: egfr, kinase, exon 20, inhibitor, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 38225.01

Authors

Beyett, T.S.,Eck, M.J. (deposition date: 2022-11-05, release date: 2023-11-08, Last modification date: 2024-11-06)

Primary citation

Zhao, H.,Beyett, T.S.,Jiang, J.,Rana, J.K.,Schaeffner, I.K.,Santana, J.,Janne, P.A.,Eck, M.J.
Biochemical analysis of EGFR exon20 insertion variants insASV and insSVD and their inhibitor sensitivity.
Proc.Natl.Acad.Sci.USA, 121:e2417144121-e2417144121, 2024

PubMed Abstract: Somatic mutations in the epidermal growth factor receptor (EGFR) are a major cause of non-small cell lung cancer. Among these structurally diverse alterations, exon 20 insertions represent a unique subset that rarely respond to EGFR tyrosine kinase inhibitors (TKIs). Therefore, there is a significant need to develop inhibitors that are active against this class of activating mutations. Here, we conducted biochemical analysis of the two most frequent exon 20 insertion variants, V769_D770insASV (insASV) and D770_N771insSVD (insSVD) to better understand their drug sensitivity and resistance. From kinetic studies, we found that EGFR insASV and insSVD are similarly active, but have lower K values compared to the L858R variant, which contributes to their lack of sensitivity to 1st-3rd generation EGFR TKIs. Biochemical, structural, and cellular studies of a diverse panel of EGFR inhibitors revealed that the more recently developed compounds BAY-568, TAS6417, and TAK-788 inhibit EGFR insASV and insSVD in a mutant-selective manner, with BAY-568 being the most potent and selective versus wild-type (WT) EGFR. Cocrystal structures with WT EGFR reveal the binding modes of each of these inhibitors and of poziotinib, a potent but not mutantselective inhibitor, and together they define interactions shared by the mutant-selective agents. Collectively, our results show that these exon20 insertion variants are not inherently inhibitor resistant, rather they differ in their drug sensitivity from WT EGFR. However, they are similar to each other, indicating that a single inhibitor should be effective for several of the diverse exon 20 insertion variants.

PubMed: 39471218
DOI: 10.1073/pnas.2417144121

Experimental method

X-RAY DIFFRACTION (2.8 Å)