Recent research conducted at MD Anderson Cancer Research Center may help in designing a potent and effective cancer treatment by shutting down the proteins responsible for the cancer promoting activities. The results of this study are published online in the scientific journal Cell.
According to researchers, they have been successful in designing a compound that can bind and block the protein that turns off cellular defenses against cancers, and switch on cancer-feeding metabolic pathways. The co author of the study, Hui-Kuan Lin, who is also an associate professor of Cellular and Molecular Oncology at MD Anderson, explained:
“The beauty of this study is we identified an inhibitor and showed how it functions to block Skp2. Inhibitors often are discovered without an initial understanding of how they work.”
Lin and Shuxing Zhang, an assistant professor of Experimental Therapeutics and head of the Integrated Molecular Discovery Laboratory at MD Anderson, have been working together to study the characteristics of the protein. He commented:
“There are many more chemical compounds available than there are estimated stars in the universe. We have a database with 10 million compounds, but our prescreening analysis narrowed our computerized search to 120,000 and then further to find small-molecule candidates that inhibit Skp2.”
They identified that the inhibitor compound can plug into critical binding sites on Skp2. This binding further prevents the protein from connecting to Skp1 and thus stops the formation of complex that promotes the cancer development.
“This compound has a high degree of specificity – our tests in prostate and lung cancer show it preferentially targets the cancer cells but not the normal cells.”
Researchers discovered that the inhibitor compound has the capacity to suppress the development of prostate cancer by suppressing prostate cancer stem cells. The mechanism suggested by Lin and colleagues indicate the promotion of cancer by:
– Initiating the cascade for the destruction of p27 — the cancer-stifling protein that renders cells senescent, or incapable of dividing.
– Initiating the glycolytic pathway for the generation of energy for metabolizing and dividing cancer cells.
The researchers also suggested that glycolytic pathway is responsible for Herceptin resistance and shorter survival among breast cancer patients since tumor cells express HER2 protein.
During the analysis, the researchers identified the pocket-like region where the two proteins meet to form a complex. Zhang suggested that, theoretically, Skp2 can be the ideal target, but since the binding area is large and targeting protein-protein interaction is also difficult, the research team finally produced the compound SZL-P1-41 (also known as Compound #25) that can block the site of interaction of two proteins.
“To begin such a search, to rationally design a drug, you must first understand the target’s biology and then look at its structure and fully comprehend its complex interactions and how disrupting those will help treat the disease. Once you understand those, you’re ready to screen using computer models.”
Later experimentation confirmed that the Compound #25 has the capacity to selectively destroy prostate cancer cells with little to no effect on the surrounding normal tissue. Future experiments were also helpful in confirming the drug effectiveness in two lung cancer cell lines and in liver and osteocarcinoma cell lines.
In order to manage the issue of drug resistance, the researchers treated the cancer cell lines with Compound #25 and chemotherapeutic agents like cyclophosphamide or doxorubicin and identified that the combination of drugs tripled the inhibition of cancer cells when compared to doxorubicin alone and doubled to cyclophosphamide alone.
The results of the experimentation performed in animal models (mice) indicated promising results in both prostate and lung tumors, with reduction in the size of tumor to about a quarter with Compound # 25 when compared to control agent.
Photo from wikipedia.org