SYNTHETIC AND MECHANISTIC STUDIES OF PRECIOUS METAL-MODIFIED TYROSINE KINASE INHIBITORS

Molecularly targeted therapies such as tyrosine kinase inhibitors (TKIs) make up an important class of oncology drugs. Targeting of cancer cells harboring oncogenic molecular targets, especially signaling kinases, with precision medicines, while sparing the majority of normal healthy cells, has led to promising new treatments for cancer patients. Simple metal complexes and metal–organic hybrid agents have been investigated as anti-cancer therapies but their applications in targeted therapies remain to be explored. The goal of the research described in this dissertation was to design metal-modified ErbB kinase inhibitors as potential targeted anticancer therapies. Combining the binding selectivity of kinase inhibitors with the adduct-forming properties of precious metal-based electrophiles (Au, Pt) in a hybrid molecule is a previously unexplored concept. To achieve this, thiourea-modified 3-chloro-4-fluoroanilino-quinazoline derivatives were first studied as epidermal growth factor receptor (EGFR) tyrosine kinase-targeted carrier ligands in linear gold(I) complexes. The molecules mimic the EGFR inhibitor gefitinib. Gold(I) complexes were generated using simple ligand-exchange reactions, and the biological activity of the carrier ligands and corresponding complexes was studied in cancer cells using colorimetric cell viability assays. A thiourea with an extended linker was able to partially overcome resistance to gefitinib in NCI-H1975 lung cancer cells expressing EGFRL858R/T790M double mutant. The corresponding [Au(PEt3)] complex maintains activity at low-micromolar concentrations similar to the metal-free carrier. Both compounds inhibit EGFR kinase-mediated phosphorylation with submicromolar IC50 values similar to those observed for gefitinib (ADP-glo assay). While the [Au(PEt3)]-modified inhibitor promoted adduct formation with cysteine thiol in a model peptide (ESI MS), the compound was too reactive for further preclinical development.

Grantor dc:publisher

Wake Forest University

Year dc:date.issued

2017

Author dc:creator

• Yang, Mu

• Anti-cancer

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/10339/89873

OAI identifier oai:identifier

oai:wakespace.lib.wfu.edu:10339/89873