8FV3

EGFR(T790M/V948R) in complex with compound 1 (LN4503)

Summary for 8FV3

• Entry DOI: 10.2210/pdb8fv3/pdb
• Descriptor: Epidermal growth factor receptor, MAGNESIUM ION, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (5 entities in total)
• Functional Keywords: inhibitor, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 152073.60

Authors

Ogboo, B.C.,Heppner, D.E. (deposition date: 2023-01-18, release date: 2024-01-17, Last modification date: 2024-03-20)

Primary citation

Wittlinger, F.,Ogboo, B.C.,Shevchenko, E.,Damghani, T.,Pham, C.D.,Schaeffner, I.K.,Oligny, B.T.,Chitnis, S.P.,Beyett, T.S.,Rasch, A.,Buckley, B.,Urul, D.A.,Shaurova, T.,May, E.W.,Schaefer, E.M.,Eck, M.J.,Hershberger, P.A.,Poso, A.,Laufer, S.A.,Heppner, D.E.
Linking ATP and allosteric sites to achieve superadditive binding with bivalent EGFR kinase inhibitors.
Commun Chem, 7:38-38, 2024

PubMed Abstract: Bivalent molecules consisting of groups connected through bridging linkers often exhibit strong target binding and unique biological effects. However, developing bivalent inhibitors with the desired activity is challenging due to the dual motif architecture of these molecules and the variability that can be introduced through differing linker structures and geometries. We report a set of alternatively linked bivalent EGFR inhibitors that simultaneously occupy the ATP substrate and allosteric pockets. Crystal structures show that initial and redesigned linkers bridging a trisubstituted imidazole ATP-site inhibitor and dibenzodiazepinone allosteric-site inhibitor proved successful in spanning these sites. The re-engineered linker yielded a compound that exhibited significantly higher potency (~60 pM) against the drug-resistant EGFR L858R/T790M and L858R/T790M/C797S, which was superadditive as compared with the parent molecules. The enhanced potency is attributed to factors stemming from the linker connection to the allosteric-site group and informs strategies to engineer linkers in bivalent agent design.

PubMed: 38378740
DOI: 10.1038/s42004-024-01108-3

Experimental method

X-RAY DIFFRACTION (2.1 Å)