The scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.
The research team spent four years working to understand how the compound PCLX-001 targets enzymes that perform myristoylation, a cellular process in which the fatty acid myristate modifies proteins so they can move to membranes and become part of the cell signalling system.
"The enzymes that transfer myristate onto proteins are overexpressed in some cancer cells, meaning there's more of those enzymes, so they have long been thought of as a logical target for cancer treatment," said the senior author.
"Until now no one has done a thorough analysis of this hypothesis," the author said. "We actually found that several types of cancer cells have fewer of these enzymes, making them seemingly easier to kill with our lead drug."
To demonstrate this, the researchers tested the drug against 300 different cancer cell types. They reported that blood cancer cells including lymphomas and leukemia, which have fewer of the enzymes, are extremely sensitive to the drug. It also killed other types of cancer cells when given at a higher concentration.
The team found that the drug stopped B-cell lymphoma tumour survival signals, killed B-cell tumour cells in both test-tube and animal experiments, and left non-cancerous cells unharmed, the author said. In addition to abrogating myristoylation of Src family kinases, PCLX-001 also promotes their degradation and, unexpectedly, that of numerous non-myristoylated BCR effectors including c-Myc, NFκB and P-ERK, leading to cancer cell death.
Having completed the necessary biosafety studies, the company plans to initiate Phase 1 trials of PCLX-001 in lymphoma, leukemia, breast and colon cancer patients.
"We think PCLX-001 is a compound with a large therapeutic window that can kill the cancer cells at a much lower concentration than what is needed to kill normal cells," he said. "That is the holy grail of cancer therapies." "Because of the highly selective nature of our drug, it's often referred to as a precision medicine, and we anticipate minimal side-effects," the author said.
Compound that specifically targets protein myristoylation protects against blood cancer
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