CU Cancer Centre scientists recently demonstrated how a new cancer drug can slow the progression of cancer cells, by inhibiting the oncogene CHD1L, which is a chromatin remodelling enzyme that aids tumour progression and metastasis in many cancer types.
How was this new cancer drug developed?
An enzyme that has been identified as instrumental in the progression of many types of cancers has had its inhibitors synthesised and evaluated by University of Colorado (CU) Cancer Centre researchers. This investigation has led to the development of a new cancer drug.
This study has been recently published in the Journal of Medicinal Chemistry, and researchers detailed more than 30 inhibitors that are synthesised to resist the tumour-causing effects of the CHD1L oncogene, which has been implicated in tumour progression, multidrug resistance, and metastasis in many types of cancer.
“There are no known CHD1L inhibitors reported in the literature,” explained Daniel LaBarbera, corresponding author, PhD, and a CU Cancer Centre Member and Director of the Centre for Drug Discovery in the Skaggs School of Pharmacy and Pharmaceutical Sciences. “We have the only known drug leads against this oncogene, so we optimized one of our top lead compounds through drug design and medicinal chemistry with the goal of improving its efficacy and drug-like properties in targeting the CHD1L oncogene.”
What is CHD1L?
CHD1L, also known as ALC1, was discovered in 2008 and within two years emerged as a novel oncogene. “It is over-expression or over-amplification in many cancers is associated with poor prognosis and with late-stage metastatic cancer,” said LaBarbera, Co-Director of the Drug Discovery, and Development Shared Resource (D3SR). The D3SR is the main infrastructure of the CU Anschutz Medical Campus Centre for Drug Discovery and is a CU Cancer Centre-supported shared resource lab. “It helps tumour cells progress and then become drug resistant.”
Additionally, tumour cells require transcription factors to access sites on DNA, which they can then bind to, and activate gene expression. CHD1L is recruited to essentially remodel DNA structure and expose these sites. Inhibiting CHD1L has the potential to reverse this malignant cellular state to one that is less tumorigenic and more sensitive to clinical therapies.
How did this contribute to the creation of the novel drug?
Scientists employed a well-known drug lead that demonstrated promise against CHD1L, and after screening approximately 20,000 drug compounds, researchers modified the drug structure to synthesise analogues that would improve the drug’s efficacy against CHD1L.
They also performed molecular modelling utilising a recently published CHD1L crystal structure to explain how the drug binds to the CHD1L enzyme. One of the most promising analogues – known as 6.11 – was also one of the simplest. This is because researchers added a bromine atom to the base drug, which improved its drug-like properties significantly.
“Oftentimes, if drugs are rapidly metabolized in the liver, they lose their activity and are excreted out of the body,” LaBarbera noted. “Incorporating bromine into the design improved the metabolic stability compared to the parent lead drug 6.0, which translated to an almost three-fold longer half-life in animals. We went from three hours of half-life in blood plasma with 6.0 to an eight-hour half-life with 6.11.”
The increased half-life is significant because it could lead to more effective drug treatment in humans. “It represents the possibility that a patient could receive treatment once a day instead of twice a day. We also showed that the drugs could be administered orally and still get to the tumour site and have anti-tumour activity,” LaBarbera added.
“There is the potential of developing a pill formulation for this drug that could supplement and synergise with intravenous chemotherapy and other standard of care therapies.”
When will this be applied in healthcare settings?
Scientists are continuing to investigate developing CHD1L inhibitors and are currently considering how the drug could be utilised in combination with standard of care therapies: “Including radiation and other therapies, where a patient would go home with a prescription for the drug and take it to help prime tumours, wherever they are in the body, for chemotherapy,” LaBarbera concluded.
The CHD1L enzyme is essential for DNA repair in tumour cells, which is a major mechanism of drug resistance. Interestingly, researchers have observed that the enzyme’s expression is upregulated in tumour cells, which means they can make more targeted therapies with the possibility of fewer side effects.
Researchers are continuing to work with the 6.11 analogue, which has shown the most promising biological activity, but also new analogues for the development of US FDA investigational studies, further supporting CU as a leader in drug discovery.
This research is supported by a five-year R01 grant from the National Institutes of Health, National Cancer Institute, and previous funding from the CU Cancer Centre Developmental Therapeutics seed grant, as well as a seed grant from the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences ADR fund.