Redox Regulation of Epidermal Growth Factor Receptor Signaling through Cysteine Oxidation

Truong, Thu H.; Carroll, Kate S.

doi:10.1021/bi301441e

Cited by 163 publications

(142 citation statements)

References 130 publications

(263 reference statements)

Supporting

Mentioning

137

Contrasting

Unclassified

Order By: Relevance

“…A deeper exploration of Cys oxidation in relation to metal binding properties could open up new vistas on redox signaling. Finally, the development of drugs that specifically target different oxidation states of proteins would appear to be a worthwhile goal (79).…”

Section: Discussionmentioning

confidence: 99%

The Redox Biochemistry of Protein Sulfenylation and Sulfinylation

Conte

Carroll

2013

Journal of Biological Chemistry

Self Cite

276

220

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

The Redox Biochemistry of Protein Sulfenylation and Sulfinylation

Conte

Carroll

2013

Journal of Biological Chemistry

Self Cite

276

220

View full text Add to dashboard Cite

“…There is a growing appreciation that oxidation of cysteine residues affects signaling networks (19)(20)(21), including a report that EGFR is oxidized by hydrogen peroxide (H 2 O 2 ) at Cys 797 (the reactive nucleophile) (22,23). Because oxidation fundamentally affects the chemical properties of the cysteine thiol by transforming it to either a highly polar oxo-acid or a bulky glutathione adduct, the EGFR active site topography and conformation may be affected.…”

Section: Significancementioning

confidence: 99%

Covalent EGFR inhibitor analysis reveals importance of reversible interactions to potency and mechanisms of drug resistance

Schwartz¹,

Kuzmič²,

Solowiej³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

236

252

View full text Add to dashboard Cite

Covalent inhibition is a reemerging paradigm in kinase drug design, but the roles of inhibitor binding affinity and chemical reactivity in overall potency are not well-understood. To characterize the underlying molecular processes at a microscopic level and determine the appropriate kinetic constants, specialized experimental design and advanced numerical integration of differential equations are developed. Previously uncharacterized investigational covalent drugs reported here are shown to be extremely effective epidermal growth factor receptor (EGFR) inhibitors (k inact /K i in the range 10), despite their low specific reactivity (k inact ≤ 2.1 × 10), which is compensated for by high binding affinities (K i < 1 nM). For inhibitors relying on reactivity to achieve potency, noncovalent enzyme-inhibitor complex partitioning between inhibitor dissociation and bond formation is central. Interestingly, reversible binding affinity of EGFR covalent inhibitors is highly correlated with antitumor cell potency. Furthermore, cellular potency for a subset of covalent inhibitors can be accounted for solely through reversible interactions. One reversible interaction is between EGFRCys 797 nucleophile and the inhibitor's reactive group, which may also contribute to drug resistance. Because covalent inhibitors target a cysteine residue, the effects of its oxidation on enzyme catalysis and inhibitor pharmacology are characterized. Oxidation of the EGFR cysteine nucleophile does not alter catalysis but has widely varied effects on inhibitor potency depending on the EGFR context (e.g., oncogenic mutations), type of oxidation (sulfinylation or glutathiolation), and inhibitor architecture. These methods, parameters, and insights provide a rational framework for assessing and designing effective covalent inhibitors.cysteine oxidation | protein kinase | signaling | capture period | warhead interactions R eceptor tyrosine kinases, such as the epidermal growth factor receptor (EGFR) tyrosine kinase, catalyze protein phosphorylation reactions to trigger signaling networks. Oncogenic activating mutations of EGFR lead to aberrant signaling for a subpopulation (10-30%) of nonsmall cell lung cancer patients (1). These mutations reside primarily in two regions of the EGFR catalytic domain [namely, the in-frame deletion mutations (e.g., Del746-750) preceding the N-terminal Cα-helix (exon 19) and the C-terminal activation loop L858R mutation (exon 21)] (2). Patients harboring these activating mutations usually respond to reversible ATP competitive drugs (e.g., erlotinib and gefitinib), but their effectiveness is limited by the emergence of drug resistance, in part, through an additional active site mutation (T790M and gatekeeper residue) in 50% of the responsive patients (3).A second generation of drug discovery dating back to the 1990s resulted in inhibitors that incorporate a chemically reactive Michael Acceptor (MA) electrophile (warhead) to target a cysteine nucleophile (EGFR-Cys 797 ) in the hinge region of the ATP binding cleft (4). The ...

show abstract

“…Here, the binding of extracellular growth factor ligands to receptor tyrosine kinases (RTKs) on the cell surface frequently co-activates members of the NADPH oxidase (Nox) family [8][9][10] protein tyrosine phosphatases (PTPs) on a reactive cysteine in their active site [11,12].…”

Section: Principles Of Reduction-oxidation Signalingmentioning

confidence: 99%