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New Leukemia Target, Drug Candidate Discovered

Acute myeloid leukemia cells

Acute myeloid leukemia cells (Cancer Genome Atlas, NIH)

6 July 2016. An industry-academic research team identified a new target for acute myeloid leukemia, and tested a new drug that in lab cultures stops the growth of these cancer cells. The team from Cold Spring Harbor Laboratory in New York and drug maker Boehringer Ingelheim in Germany published their findings Monday in the journal Nature Chemical Biology (paid subscription required).

Cold Spring Harbor researcher Christopher Vakoc and colleagues are seeking more effective treatments for acute myeloid leukemia, a cancer of the blood and bone marrow that worsens quickly if left untreated. As the disease develops, bone marrow produces abnormal white blood stem cells called myeloblasts that do not mature into normal functioning white blood cells.

The excessive growth of abnormal myeloblasts crowds out healthy white, red, and platelet blood cells, and can spread to other parts of the body. Leukemia and Lymphoma Society says acute myeloid leukemia has a 5-year survival rate of 26 percent in the U.S., although for children and teens under the age of 15, about two-thirds (67%) survive for at least 5 years.

Vakoc and colleagues identified the Bromodomain Containing 9 or BRD9 gene that modifies chromatin — the substance in cells with a nucleus that form chromosomes — as a leading enabler of this blood cancer, which depends on BRD9 for its unimpeded growth. To address this gene, however, the team needed a more precise target and identified a pocket formed by a mutation in BRD9 that protects leukemia cells from the body’s built-in checkpoints that fight these attackers. The BRD9 mutation activates proteins from the MYC gene that enables the unchecked proliferation of leukemia cancer cells.

A chemistry lab at Boehringer Ingelheim headed by co-author Manfred Koegl developed a candidate drug code-named BI-7273 that targets the BRD9 pocket. In tests with mouse and human acute myeloid leukemia cells in lab cultures, the researchers found BI-7273 prevents activation of the MYC gene, and limits proliferation of leukemia cells.

The team, however, still had to show the limits on leukemia cells were caused by BI-7273 hitting the BRD9 pocket, and not some other coincidental action. To show the drug candidate works as intended, the researchers engineered the bromodomain protein pocket to resemble a similar pocket in a related chromatin-modifying protein BRD4.

While the pockets in the two proteins are similar they are shaped differently. Tests with acute myeloid leukemia cell cultures show BI-7273 does not stop activation of the MYC gene and proliferation of leukemia cells in the BRD4-engineered pocket, as it does with BRD9 pockets. These results support the earlier findings that BI-7273 hits the BRD9 pocket and works as intended with acute myeloid leukemia cells.

The team conducted other experiments with swapping engineered proteins for native types as a way of testing drug candidates that target precise binding sites, which they consider as important as identifying a new drug candidate. “Here we’ve described a simple new approach that can unambiguously assign the therapeutic effect of a drug to a single binding site,” says Vakoc in an Cold Spring Harbor statement. “As the age of precision medicine begins, this is an important issue, a matter of sink or swim for some candidate drugs.”

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