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Characterization of Covalent-Reversible EGFR Inhibitors.

ABSTRACT: Within the spectrum of kinase inhibitors, covalent-reversible inhibitors (CRIs) provide a valuable alternative approach to classical covalent inhibitors. This special class of inhibitors can be optimized for an extended drug-target residence time. For CRIs, it was shown that the fast addition of thiols to electron-deficient olefins leads to a covalent bond that can break reversibly under proteolytic conditions. Research groups are just beginning to include CRIs in their arsenal of compound classes, and, with that, the understanding of this interesting set of chemical warheads is growing. However, systems to assess both characteristics of the covalent-reversible bond in a simple experimental setting are sparse. Here, we have developed an efficient methodology to characterize the covalent and reversible properties of CRIs and to investigate their potential in targeting clinically relevant variants of the receptor tyrosine kinase EGFR.

SUBMITTER: Smith S

PROVIDER: S-EPMC6018958 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Characterization of Covalent-Reversible EGFR Inhibitors.

Smith Steven S Keul Marina M Engel Julian J Basu Debjit D Eppmann Simone S Rauh Daniel D

ACS omega 20170420 4

Within the spectrum of kinase inhibitors, covalent-reversible inhibitors (CRIs) provide a valuable alternative approach to classical covalent inhibitors. This special class of inhibitors can be optimized for an extended drug-target residence time. For CRIs, it was shown that the fast addition of thiols to electron-deficient olefins leads to a covalent bond that can break reversibly under proteolytic conditions. Research groups are just beginning to include CRIs in their arsenal of compound class ...[more]

PMID: 29963651

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