A selective S-acyltransferase inhibitor suppresses tumor growth.
Jia-Ying LeeSebastian DilonesTimothe MaujeanMohammad AsadAltaf MohdNoam AuslanderDonita C BradyGeorge M BurslemEric S WitzePublished in: bioRxiv : the preprint server for biology (2024)
S-acyltransferases play integral roles in essential physiological processes including regulation of oncogenic signaling pathways. While discovered over 40 years ago the field still lacks specific S-acylation inhibitors thus the potential benefit of pharmacologically targeting S-acyltransferases for human disease is still unknown. Here we report the identification of an orally bioavailable acyltransferase inhibitor SD-066-4 that inhibits the acyltransferase ZDHHC20. We identified a specific alanine residue that accommodates the methyl group of SD-066-4, thus providing isoform selectivity. SD-066-4 stably reduces EGFR S-acylation in Kras mutant cells and blocks the growth of Kras mutant lung tumors extending overall survival. We find that lung cancer patients harboring deletions in ZDHHC20 or ZDHHC14 concurrent with Kras alterations have a significant survival benefit, underscoring the translational importance of these enzymes.
Keyphrases
- wild type
- signaling pathway
- induced apoptosis
- small cell lung cancer
- endothelial cells
- free survival
- cell cycle arrest
- epidermal growth factor receptor
- induced pluripotent stem cells
- locally advanced
- epithelial mesenchymal transition
- human health
- cell proliferation
- amino acid
- risk assessment
- bioinformatics analysis