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T-00423: NOVEL CUCURBITACIN-INSPIRED ESTRONE DRUG CANDIDATES FOR TREATMENT OF HEPATOCELLULAR CARCINOMA

Background: Hepatocellular carcinoma (HCC) is a malignancy of liver cells caused by factors including liver infections, excessive alcohol use and cirrhosis. It is commonly found in Asia and Africa where liver infections such as hepatitis B and C predispose people to the disease. According to Cancer Statistics Center new cases of liver and intrahepatic bile duct cancer in U.S.A is estimated to reach 40,710 with an estimated 28,920 deaths in 2017. Progression of the disease is linked to overexpression and aberrant function of epidermal growth factor receptor (EGFR). EGFR is a single-pass transmembrane tyrosine kinase receptor required for differentiation, growth and survival of cells. Moreover, malfunction of the receptor is linked to progression of other malignancies including ovarian, breast and prostate cancers. Current treatment strategies for HCC include local ablation therapy, surgical resection and liver transplantation. As part of the global effort to combat HCC, researchers at SDSU are developing estrone analogs as potential chemotherapeutic agents. Estrone is a naturally occurring steroid found in both males and females. The design is based on the structure and function of cucurbitacins (CUCs), which are natural product compounds found in plants belonging to the cucurbitaceae family including gourds and pumpkins. CUCs have a core structure similar to estrone and they are known to possess anti-inflammatory and antitumor properties. Current chemotherapeutic strategies for treating HCC are usually hampered by tumor resistance amid other negative side effects. The motivation for this work is to increase the pool of therapeutic agents available for treating HCC and to develop potent drugs with minimal side effects on patient health during chemotherapy and overcome drug resistance.

Description: Researchers designed cucurbitacin inspired-estrone analogs (CIEAs) by exploiting the structural similarity between estrone and CUCs. In silico drug design strategies were used to extensively study binding and inhibitory properties of CIEAs on EGFR kinase activity. A number of novel candidates with efficient binding properties to the kinase domain have been synthesized. MMA 132, one of the synthesized CIEAs, has shown remarkable inhibition of HCC cell line HepG2 at IC50 value of 2 µM, at least 12 times the inhibitory effect of standard Erlotinib (with IC50 of 25 µM). Further studies has confirmed binding of MMA 132 to the kinase domain of EGFR and concomitant inhibition of about 90% of its phosphorylase activity. In addition, MM132 significantly inhibit phosphorylation of BRAF, ERK, MEK signal domain, arrest HCC at G1 phase and inhibit cell migration respectively. Phosphorylation of specific tyrosine residues in the EGFR kinase domain is required for activation of the receptor to trigger signaling cascades that promote growth and survival of cells. Thus unregulated signaling from an activated receptor promotes the growth and progression of tumor cells. Therefore MMA 132 is a promising inhibitor of aberrant EGFR kinase activity making it a great candidate for therapeutic intervention of HCC.

Advantages: MMA 132 and its novel counterpart analogs will increase the pool of therapeutic agents for developing efficient treatment strategies for HCC patients. The mechanism of action of MMA 132 makes it a suitable candidate for development as a multikinase inhibitor, which will extend its application to other types of cancers including colon, breast, ovarian and skin cancers.