5Y25

EGFR kinase domain mutant (T790M/L858R) with covalent ligand NS-062

Summary for 5Y25

• Entry DOI: 10.2210/pdb5y25/pdb
• Descriptor: Epidermal growth factor receptor, (2R)-N-[4-[(3-chloranyl-4-fluoranyl-phenyl)amino]-7-(3-morpholin-4-ylpropoxy)quinazolin-6-yl]-1-(2-fluoranylethanoyl)pyrrolidine-2-carboxamide (2 entities in total)
• Functional Keywords: inhibitor, complex, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 38741.19

Authors

Shiroishi, M.,Abe, Y.,Caaveiro, J.M.M.,Sakamoto, S.,Morimoto, S.,Fuchida, H.,Shindo, N.,Ojida, A. (deposition date: 2017-07-24, release date: 2018-07-25, Last modification date: 2024-10-23)

Primary citation

Shindo, N.,Fuchida, H.,Sato, M.,Watari, K.,Shibata, T.,Kuwata, K.,Miura, C.,Okamoto, K.,Hatsuyama, Y.,Tokunaga, K.,Sakamoto, S.,Morimoto, S.,Abe, Y.,Shiroishi, M.,Caaveiro, J.M.M.,Ueda, T.,Tamura, T.,Matsunaga, N.,Nakao, T.,Koyanagi, S.,Ohdo, S.,Yamaguchi, Y.,Hamachi, I.,Ono, M.,Ojida, A.
Selective and reversible modification of kinase cysteines with chlorofluoroacetamides.
Nat.Chem.Biol., 15:250-258, 2019

PubMed Abstract: Irreversible inhibition of disease-associated proteins with small molecules is a powerful approach for achieving increased and sustained pharmacological potency. Here, we introduce α-chlorofluoroacetamide (CFA) as a novel warhead of targeted covalent inhibitor (TCI). Despite weak intrinsic reactivity, CFA-appended quinazoline showed high reactivity toward Cys797 of epidermal growth factor receptor (EGFR). In cells, CFA-quinazoline showed higher target specificity for EGFR than the corresponding Michael acceptors in a wide concentration range (0.1-10 μM). The cysteine adduct of the CFA derivative was susceptible to hydrolysis and reversibly yielded intact thiol but was stable in solvent-sequestered ATP-binding pocket of EGFR. This environment-dependent hydrolysis can potentially reduce off-target protein modification by CFA-based drugs. Oral administration of CFA quinazoline NS-062 significantly suppressed tumor growth in a mouse xenograft model. Further, CFA-appended pyrazolopyrimidine irreversibly inhibited Bruton's tyrosine kinase with higher target specificity. These results demonstrate the utility of CFA as a new class warheads for TCI.

PubMed: 30643284
DOI: 10.1038/s41589-018-0204-3

Experimental method

X-RAY DIFFRACTION (3.102 Å)