CHD1L, also known as ALC1, was discovered in 2008 and within two years has emerged as a new oncogene. “Its overexpression or amplification in many cancers is associated with poor prognosis and late-stage metastatic cancer.“, explains LaBarbera, who is also co-director of the Drug Discovery and Development Sharing Resource (D3SR).
The D3SR is the main infrastructure of the CU Anschutz Medical Facility’s Drug Discovery Center and a shared resource laboratory supported by the Cancer Center. “It helps tumor cells progress and then become resistant. “
Tumor cells need transcription factors to access sites on DNA that they can bind to and then trigger gene expression. CHD1L is used to fundamentally modify the DNA structure and expose these sites.
Inhibition of CHD1L has the potential to reverse this malignant cellular state to a cellular state that is less tumorigenic and more sensitive to clinical therapies.
Working with a known and promising lead drug against CHD1L, after screening about 20,000 drug compounds, the researchers modified the drug structure to synthesize analogues that improve the effectiveness of the drug. drugs for CHD1L.
They also performed molecular modeling using the recently published CHD1L crystal structure to explain how the drug binds to the CHD1L enzyme.
One of the most promising analogues, called 6.11, is also one of the simplest: The researchers added a bromine atom to the generic drug, greatly improving the drug’s drug-like properties. it.
“Normally, if drugs are rapidly metabolized in the liver, they lose their activity and are eliminated from the body“LaBarbera said.”Incorporation of bromine into the design improved metabolic stability over the parent drug 6.0, resulting in an almost three-fold longer half-life in animals. We went from a plasma half-life of 3 hours with 6.0 to a half-life of 8 hours with 6.11. “
The increased half-life is important because it could lead to more effective drug therapy in humans. “It represents the possibility that patients could be treated once a day instead of twice a day. We also show that drugs can be administered orally and still reach the tumor site and have anti-tumor activity.“LaBarbera said.
“There is potential to develop a pill formulation for this drug that could complement and synergize with intravenous chemotherapy and another standard of care.. “
As research to develop a CHD1L inhibitor continues, scientists are looking at how the drug could be used in combination with standard care therapies,”including radiation and other therapies, in which the patient goes home with a prescription and takes it to help get rid of tumors, anywhere in the body, for chemotherapy.“LaBarbera said.
The enzyme CHD1L is required for DNA repair in tumor cells, which is a key mechanism of drug resistance. Interestingly, the researchers observed that the expression of the enzyme was upregulated in tumor cells, allowing them to generate more targeted therapies with potentially fewer side effects.
Researchers are continuing to work with the 6.11 analog, which has shown the most promising biological activity, but is also the new analog to develop new US FDA investigative studies. , further supporting CU as a leader in drug discovery.