1421372-44-2Relevant articles and documents
Selective Covalent Targeting of Mutated EGFR(T790M) with Chlorofluoroacetamide-Pyrimidines
Fuchida, Hirokazu,Hosokawa, Keitaro,Inamori, Ryo,Koyanagi, Satoru,Kuwata, Keiko,Matsunaga, Naoya,Ohdo, Shigehiro,Ojida, Akio,Ono, Mayumi,Sato, Mami,Shibata, Tomohiro,Shindo, Naoya,Tokunaga, Keisuke,Watari, Kosuke,Xiao-Lin, Guo
, p. 1137 - 1144 (2020)
Covalent modification of disease-associated proteins with small molecules is a powerful approach for achieving an increased and sustained pharmacological effect. To reduce the potential risk of nonselective covalent modification, molecular design of covalent inhibitors is critically important. We report herein the development of a targeted covalent inhibitor for mutated epidermal growth factor receptor (EGFR) (L858R/T790M) using α-chlorofluoroacetamide (CFA) as the reactive group. The chemically tuned weak reactivity of CFA was suitable for the design of third-generation EGFR inhibitors that possess the pyrimidine scaffold. The structure-activity relationship study revealed that CFA inhibitor 18 (NSP-037) possessed higher inhibition selectivity to the mutated EGFR over wild-type EGFR when compared to clinically approved osimertinib. Mass-based chemical proteomics analyses further revealed that 18 displayed high covalent modification selectivity for the mutated EGFR in living cells. These findings highlight the utility of CFA as a warhead of targeted covalent inhibitors and the potential application of the CFA-pyrimidines for treatment of non-small-cell lung cancer.
Structure- and reactivity-based development of covalent inhibitors of the activating and gatekeeper mutant forms of the epidermal growth factor receptor (EGFR)
Ward, Richard A.,Anderton, Mark J.,Ashton, Susan,Bethel, Paul A.,Box, Matthew,Butterworth, Sam,Colclough, Nicola,Chorley, Christopher G.,Chuaqui, Claudio,Cross, Darren A.E.,Dakin, Les A.,Debreczeni, Judit é.,Eberlein, Cath,Finlay, M. Raymond V.,Hill, George B.,Grist, Matthew,Klinowska, Teresa C.M.,Lane, Clare,Martin, Scott,Orme, Jonathon P.,Smith, Peter,Wang, Fengjiang,Waring, Michael J.
, p. 7025 - 7048 (2013/10/01)
A novel series of small-molecule inhibitors has been developed to target the double mutant form of the epidermal growth factor receptor (EGFR) tyrosine kinase, which is resistant to treatment with gefitinib and erlotinib. Our reported compounds also show selectivity over wild-type EGFR. Guided by molecular modeling, this series was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and demonstrates high levels of activity in cellular models of the double mutant form of EGFR. In addition, these compounds show significant activity against the activating mutations, which gefitinib and erlotinib target and inhibition of which gives rise to their observed clinical efficacy. A glutathione (GSH)-based assay was used to measure thiol reactivity toward the electrophilic functionality of the inhibitor series, enabling both the identification of a suitable reactivity window for their potency and the development of a reactivity quantitative structure-property relationship (QSPR) to support design.
