When we think of common treatments for cancer, strong medicine and radiation are typically at the top of the list. Muhammad Murtaza Hassan, a Ph.D. student in the Gunning Lab at UTM, thinks differently. In Hassan’s research, he uses the process of fitting together geometric shapes to selectively inhibit the action of HDAC8, a protein associated with cancer. His novel and insurgent method of analyzing this protein caused him to make a discovery that could revolutionize cancer treatments. In June, Hassan’s study was published in the Journal of Medicinal Chemistry in the American Chemical Society (ACS).
The National Cancer Institute identifies the following cancer treatments: surgery, radiation therapy, chemotherapy, immunotherapy, targeted therapy, hormone therapy, stem cell transplants, and precision medicine. Each of these comes with a specific set of challenges and side effects. Radiation therapy and chemotherapy can damage healthy cells in addition to the cancer cells, which can cause numerous side effects, notably fatigue. Immunotherapy can cause flu-like symptoms, nausea, and dizziness. Targeted therapy can cause liver problems and diarrhea, while hormone therapy can result in sexual side effects. Other effects for current cancer treatments include, but are not limited to, anemia, fertility issues, memory issues, nerve issues, insomnia, and delirium. Scientists like Hassan are currently conducting ground-breaking research to identify new methods of treating cancer and improving the quality of life for patients enduring these side effects.
Among the causes of cancer, the cancer proteins, Histone Deacetylases (HDACs), are noteworthy. The abundance and protein activity of certain Histone Deacetylases are implicated in certain types of cancers. For instance, HDAC2 is involved in carcinogenesis, and several types of cancerous tissues have been found to possess higher levels of specific HDAC proteins than normal tissues.
Currently, there are four drugs approved by the United States Food and Drug Administration (FDA) that target HDACs: vorinostat (SAHA), romidepsin (FK228), belinostat (PXD101), and panobinostat (LBH-589). Each of these is non-selective, meaning they target multiple HDACs, and they come with unwanted side effects, such as diarrhea, thrombocytopenia, and anemia. Non-selective drug options are often not practical and end up damaging the health of the cancer patient, especially when compounded with other aggressive treatments.
“When medicinal chemists want to target cancer cells selectively, over healthy cells, they often target a distinguishing factor of a cancer cell over a healthy cell. What medicinal chemists do is target these proteins that are associated with these hallmarks of cancer,” says Hassan. In doing so, medicinal chemists target the actual root of the diseases without threatening the viability of healthy cells and proteins.
HDAC8, the protein that Hassan has placed great emphasis on in his research, confers specific properties of cancer. “It plays a vital role in the progression of neuroblastoma, says Hassan.” Neuroblastoma is a type of cancer that originates from immature nerve cells found in several areas of the body. Moreover, HDCA8 has also been implicated in schistosomiasis and Cornelia de Lange syndrome. When Hassan was mining through scientific literature, he found a study demonstrating how the HDAC8 enzyme has an L-shaped pocket. He combined this knowledge with the idea of Tetris, a video game from the ’80s, which involves perfectly fitting together geometric shapes.
“Tetris is perfect for [illustrating how to target HDAC8 exclusively] because you often have all these pieces that are falling, and you have to make that piece fall into that perfect pocket or that perfect puzzle. And the L-shape, you can say, is the archetypical Tetris piece.” This gave him the idea of playing molecular Tetris by building molecules that take an L-shape to lock into HDAC8’s L-shaped pocket and prevent it from carrying out its function. He found the perfect piece, containing zinc-binding groups that fit into the HDAC8 pocket and inhibited their functioning.
Source: https://pubs-acs-org.myaccess.library.utoronto.ca/doi/10.1021/acs.jmedchem.0c01025
“So, the way you target these enzymes is that, oftentimes, you make a molecule that fits into that tunnel, which prevents the protein from carrying out its natural function,” continues Hassan. “And when you prevent it from carrying out its natural function, you prevent it from carrying out the function that helps cancer be cancer. That, in turn, leads to killing the cancer cell or making it more sensitive to other forms of therapy.”
Confirmed by an oncologist in Germany who tested the molecules, Hassan’s inhibitor was successful in interacting with the HDAC8 protein in cancer cells and subsequently hindering their functioning.
By merging the knowledge of structural chemistry and structural biology, Hassan focused on the creation of molecules that assume a complementary shape only to the HDAC8 pocket to inhibit its function. This treatment is selective rather than indiscriminate, which can potentially allow for safer therapies with minimal side effects. As a result, cancer patients can have a greater quality of life and receive more accurate treatment.
Hassan completed his bachelor’s degree at UTM in math and chemistry and continued his master’s at York University. He likes to look at chemistry at its molecular level as similar to engineering and treat it like solving a puzzle. Furthermore, Hassan has an eagerness to discover new methods of treating cancer that minimizes side effects and revolutionizes the understanding of the mechanisms involved.
Currently, Hassan has published his research in the Journal of Medicinal Chemistry and is pursuing further research related to this process. “I’m currently working on another study looking into the biological role of these inhibitors and trying to see how applicable they are to certain diseases,” says Hassan.
