Platination of cysteine by an epidermal growth factor receptor kinase-targeted hybrid agent

Mu Yang, Hanzhi Wu, Julie Chu, Lucas A. Gabriel, Y. Kim, Karen S. Anderson, Cristina M. Furdui, Ulrich Bierbach

Research output: Contribution to journalArticlepeer-review


Hybrid molecules have been developed which are comprised of a tyrosine kinase-targeted, quinazoline-based scaffold and a flexibly linked dia(m)minechloridoPt(ii) moiety. The target compounds maintain high affinity and selectivity for ErbB family kinase proteins and one of the derivatives induces platinum adducts with a pharmacologically important cysteine residue.

Original languageEnglish (US)
Pages (from-to)7479-7482
Number of pages4
JournalChemical Communications
Issue number54
StatePublished - 2018
Externally publishedYes

Bibliographical note

Funding Information:
In this study we have demonstrated using competitive kinase binding and inhibition assays that it is possible to equip a classical TKI structure with an electrophilic platinum(II) moiety that is compatible with kinase active site recognition. In addition, we demonstrated for one of the new hybrid agents a unique mechanism that leads to the formation of a platinum(II) chelate at C797. This form of TKI-mediated delivery of a metallo-electrophile has potential applications in modulating ATP-driven kinase signaling, which contrasts other metal-based hybrid designs.14,23 Kinase cysteine is not only a pharmacologically relevant target for irreversible inhibitors. Cysteine modifications under oxidative stress conditions, for instance, have also been implicated in kinase regulation.24,25 Similarly, platination of this site by our hybrid agents may also lead to conformational changes affecting protein phosphorylation and signal transduction. In conclusion, the unique reactivity and cysteine modifications observed for the platinum-modified TKIs suggest a potential new role of platinum, the classical anticancer metal, as an electrophile in molecularly targeted drugs. The results of this study warrant future experiments to delineate structure–function relationships and the molecular mechanism of these hybrid agents in cancer cells harboring mutated EGFR kinase. This work was funded by the Wake Forest Innovation and Commercialization Services and the Wake Forest University Comprehensive Cancer Center (NCI CCSG P30CA012197).

Publisher Copyright:
© 2018 The Royal Society of Chemistry.


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