Novel Ornithine Aminotransferase Inhibitor: Potential New Treatment for Hepatocellular Carcinoma
- Technology Benefits
- First-in-class to treat HCCPromising initial animal data
- Detailed Technology Description
- Novel Ornithine Aminotransferase Inhibitor for potentialnew treatment for hepatocellular carcinoma.#therapeutics #smallmolecule #cancer #diagnostic
- *Abstract
-
Human Ornithine Aminotransferase (OAT) plays a role inregulating mitotic cell division in rapidly growing cells and, as such, is apotential target for the development of chemotherapeutic drugs. More specifically, OAT is overexpressed in hepatocellularcarcinoma (HCC) cells so its inhibition may be beneficial in HCC treatment. In collaboration with the HebrewUniversity-Hadassah Medical Center, Northwestern researchers identified anovel, low molecular-weight, and conformationally-restricted molecule named Compound2 that selectively inhibits OAT. Both Alanine-Aminotransferaseand Aspartic Acid-Aminotransferase are not inhibited by Compound 2. In addition, this compound possesses drug-likeproperties as evidenced by no inhibition of cytochrome P450 isozymes and nohERG inhibition when tested at 10 mM concentration. In addition to its pharmacologic properties, Compound2 was also investigated for its ability to suppress the growth of HCC in vitro and in vivo. They observed a significantdecrease in the secretion of a HCC biomarker, a-fetal protein (AFP), in two hepatoma cell lines aswell as in initial animal studies. Further, they found that the growth of tumors was significantly impededin the presence of Compound 2. SeeFigures A and B to the right. HCC, thesecond most common cause of death from cancer worldwide, is a highlychemotherapy- and radiotherapy-resistant cancer with only mildly effectivesystemic therapy. This novel OAT inhibitor offers a new potential treatment forHCC. Additional data also suggests thatthe inhibition of OAT may be beneficial in treating hyperammonemia by enhancingthe urea cycle to clear excess ammonia—a secondary application for Compound 2.
(A)Administration of Compound 2 suppressedserum AFP levels in vivo. Mice were treated for 27days, 3 times a week, starting 3 weeks following HCC transplantation with twodoses of 2 (0.1 mg/kg (2 μg), dark graybars; 1 mg/kg (20 μg), light gray bars), compared with untreated controls(black bars). Levels are normalized to the starting day of therapy. (B)Compound 2 suppressed tumor volume inboth treated groups (0.1 mg/kg [2 μg], dark gray bars; 1.0 mg/kg [20 μg], lightgray bars) compared to untreated controls (black
- *Inventors
- Yaron Ilan Ehud Zigmond Richard B. Silverman* Hejun Lu
- *Publications
- Zigmond E, Ben Y, Lee H, LichtensteinY, Shalev Z, Smith Y, Zolotarov L, Ziv E, Kalman R, Le H, Lu H, Silverman R andIlan Y (2015) Suppression of Hepatocellular Carcinoma by Inhibition ofOverexpressed Ornithine Aminotransferase. ACS MedChem Lett. 6:840-4.
- Country/Region
- USA
