Orally Available Small Molecule Inhibitor of SCD1 Targets Mesothelioma Metabolism, Study Finds

Orally Available Small Molecule Inhibitor of SCD1 Targets Mesothelioma Metabolism, Study Finds

New preclinical research shows that T-3764518, an orally available small molecule inhibitor of stearoyl-CoA desaturate-1 (SCD1), can block tumor growth in colon cancer and mesothelioma cell lines as well as mouse models by inhibiting cancer metabolism.

The rapid proliferation that characterizes many cancer cells means these same cells must also meet the higher energy demands of quickly multiplying cells. Many cancers are characterized by altered metabolism including higher rates of lipid biosynthesis. That makes the proteins involved in lipid biosynthesis promising therapeutic targets.

The Japanese study, “In vitro and in vivo antitumor activities of T-3764518, a novel and orally available small molecule stearoyl-CoA desaturase 1 inhibitor,” appeared in the European Journal of Pharmacology. It describes the anti-tumor properties of the T-3764518 small molecule inhibitor which decreases the activity of SCD1 — a stearoyl-CoA desaturase enzyme critical for the synthesis of fatty acid lipids. Both SCD1 expression and activity have recently been shown to accelerate cancers of the breast, bladder, gastric, prostate, colon and lung.

These findings suggest that SCD1 might serve as a valid therapeutic target for a range of cancers. This study assessed the pharmacological properties of a new SCD1 inhibitor, T-3764518, in a colon cancer cell line (HCT-116) and a mesothelioma cell line (MSTO-211H). This small molecule inhibitor has the advantage of also being orally available.

Using in vitro assays, T-3764518 was shown to bind to SCD1 and to prevent its enzymatic activity. This changed the composition of saturated and unsaturated fatty acids found in the lipids on cell membranes. This disruption of fatty acid composition ultimately resulted in increased cell death.

In HCT-116 cells, T-3764518 inhibited the growth of these cells in a concentration-dependent manner. When either HCT-116 or MSTO-211H cells were implanted into mice and allowed to develop into tumors, treatment with T-3764518 twice daily slowed tumor growth in a concentration-dependent manner — reducing tumor size in colon cancer by up to 42 percent, and up to 62 percent in the mesothelioma tumor model.

As expected, T-3764518 also altered the fatty acid composition of tumor tissues in these mouse models.

“It has become increasingly important to target modern cancer therapies to patients who are predicted to show the greatest response using sensitivity markers to optimize clinical efficacy,” said the authors, who suggested that T-3764518 warrants further development. “Identification of sensitivity markers for SCD1 inhibitors would be a key advance, facilitating further development of this approach.”

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