A gold atom inhibited two oncogenic proteins in tumor models

Preprint: A peptide carrying a gold atom inhibited two cancer-associated proteins in cells and mice

On August 28, a bioRxiv preprint described 10714–Au, a peptide carrying a single gold atom. In experiments with purified proteins and cells, the compound inhibited mutant EGFR and KRAS, proteins whose mutations promote tumor growth. In mice bearing transplanted human tumors, it slowed tumor growth. In five patient-derived tumor organoids, which are laboratory models of tumor tissue, it reduced cell viability more than a compound containing a different peptide.

Drugs commonly bind to pockets on protein surfaces. The authors tested whether a single gold atom could attach near cysteine, an amino acid whose side chain contains a sulfur atom. The same group had previously observed gold coordinating with cysteine in another protein. In the new study, the authors tested whether they could deliver gold into tumor cells and use this interaction to target two proteins.

The researchers selected EGFR, a receptor on the cell surface, as the delivery target. A computational model proposed about 12 thousand peptides that could bind EGFR. The authors evaluated the candidates using computational analyses and laboratory experiments, then selected 10714. Blocking clathrin-dependent uptake, one of the pathways through which cells internalize substances, reduced the uptake of 10714–Au and the accumulation of gold.

In crystal structures, the gold atom was located near Cys797 in EGFR and Cys12 in KRAS, close to nucleotide-binding sites. Nucleotides are molecules involved in switching the activity of these proteins. The authors propose that coordination holds the proteins in an inactive state. Replacing Cys797 with serine abolished the inhibition of EGFR by 10714–Au.

In cells with EGFR and KRAS mutations, 10714–Au reduced growth signaling and cell viability more than the control compound GE11–Au, which contained a different peptide. The researchers then administered 10714–Au to mice bearing tumors grown from two human lung cancer cell lines and tested it in five patient-derived tumor organoids. Tumor growth in mice slowed as the dose increased, and 10714–Au reduced cell viability in the organoids more than GE11–Au.