On May 8, 2024 Pacylex Pharmaceuticals Inc. (Pacylex) is a clinical-stage pharmaceutical company developing N-myristoyltransferase (NMT) inhibitors as targeted therapies for the treatment of hematologic cancers and solid tumors, reported the publication of a new study in the Journal of Translational Medicine, "Multiomics analysis identifies oxidative phosphorylation as a cancer vulnerability arising from myristoylation inhibition," describing how NMT inhibition by zelenirstat affects cancer cells, with broad implications for multiple liquid and solid tumor cancers (Press release, Pacylex Pharmaceuticals, MAY 8, 2024, View Source [SID1234645050]).
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In order to understand how zelenirstat kills cancer cells, Pacylex researchers used mass spectrometry to identify the proteins most affected by zelenirstat treatment. They discovered that NDUFAF4, a protein essential for mitochondrial energy production from oxygen (oxidative phosphorylation), was the most severely affected of all. Inhibiting myristoylation of NDUFAF4 shut down oxidative phosphorylation in cancer cells. The study also produced an in vitro myristoylation inhibition sensitivity signature comprising 54 genes (MISS-54) enriched in hematologic cancers as well as testis, brain, lung, ovary, and colon cancers.
"The ability of a myristoylation inhibitor to limit oxidative phosphorylation and also inhibit cancer cell signaling appears to explain how zelenirstat selectively kills cancer cells, especially those with high MISS-54 scores," said Dr. Luc Berthiaume, CSO of Pacylex Pharmaceuticals. "Since normal cells readily use other non-oxidative metabolic processes to produce energy, while many types of cancer cells including relapse causing cancer stem cells cannot, zelenristat could lead to more tolerable and durable cancer treatments."
"This new mechanism of action may explain why zelenirstat treatment shows activity across multiple patients with unrelated cancers. The phase I population was an unselected group that had no remaining standard therapy options, yet zelenirstat therapy produced prolonged stable disease or better in 57% of the patients receiving the recommended Phase 2 dose," said Dr. John Mackey, CMO of Pacylex Pharmaceuticals.
Zelenirstat is currently being dosed in patients in two Phase 2a studies, in refractory and relapsed B-cell non-Hodgkin’s lymphoma and in advanced refractory colorectal cancer patients, at 4 clinical sites in Canada.