Novel Multi-Isoform ALDH Inhibitor

ID# 2019-4899
Reduction in Tumor Volume

Technology Summary

Aldehyde dehydrogenases (ALDH) are a major enzyme family that contributes to cancer progression and therapy resistance. The inventors have created a novel suite of potent multi-ALDH isoform inhibitors, which target ALDH1A1, 2, and 3A1. The most potent compound (KS100) demonstrates IC50s under 6 µM in several cancer cell models. The inhibitors cause increased ROS activity, lipid peroxidation, and toxic aldehyde accumulation. Multi-ALDH isoform inhibition also increases apoptosis and G2/M cell cycle arrest.

KS100 toxicity was mitigated by development of a nanoliposomal formulation, called NanoKS100. NanoKS100 had a loading efficiency of approximately 69% and stable long-term at 4°C. NanoKS100 administered intravenously at a submaximal dose was effective at inhibiting xenografted melanoma tumor growth by ~65% without toxicity. Animal studies demonstrate minimal weight loss and no mortality.

Application & Market Utility

ALDH overexpression is associated with a poor prognosis in many cancer types, including breast, lung, melanoma, and pancreatic cancer. Cancer cells with a stem-cell-like phenotype often express high levels of ALDH. ALDH activity has additionally been linked to the induction of an immunosuppressive tumor microenvironment.

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