Benjamin Ebert, MD, PhD, a hematologist and oncologist for the Department of Medicine at the Brigham, and his colleagues have looked at the mechanism of action of lenalidomide, a derivative of the 1950s morning sickness drug that caused birth malformations called thalidomide. It is effective in treating myelodysplastic syndrome (MDS). The syndrome encompasses a group of cancers that prevent immature blood cells to mature in good health within bone marrow. The team’s findings appear in Nature.

The main focus of the published paper is the understanding lenalidomide’s role in MDS. Ebert and colleagues have found that the drug compound is able to degrade a protein encoded by a gene found on chromosome 5q. When this protein is degraded, it induces cytogenetic remission, an elimination of malignant cells, in more than 50 percent of patients. Lenalidomide is the first case uncovered of a cancer drug functioning through a CYCLOPS mechanism. CYCLOPS genes, named in reference to the one-eyed mythical beast since CYCLOPS genes have one functional copy instead of two, are potentially targeted genes for cancer drugs since cancer cells are dependent on them for their single copy and often sit next to hard to target tumor suppressing genes.

Ebert’s team has determined that lenalidomide and other related compounds like thalidomide and pomalidomide are ineffective in mouse models. The mouse genome contains a single amino acid difference for the CRBN protein – the protein to which lenalidomide and related compounds bind. The team is currently working to use this knowledge to determine if this difference may help explain why thalidomide was initially declared safe after pre-clinical studies.

In the 1950s and 60s, thalidomide did “not cause teratogenicity in mice [but] was approved for use in pregnant women, leading to the birth of more than 10,000 newborns with limb malformations and other disabilities,” Ebert wrote.

The paper closes with the researchers stating that their findings “provide evidence that thalidomide-related molecules have distinct biological activities, mediated by degradation of distinct sets of substrates, and that these compounds will be the first in a larger class of drugs with therapeutic utility through the targeting of specific proteins for degradation.”