and Jolanta Grembecka, PhD
Photo courtesy of the
University of Michigan
Two small-molecule inhibitors can fight aggressive, acute leukemias by targeting a protein-protein interaction, according to preclinical research published in Cancer Cell.
The compounds, MI-463 and MI-503, work by inhibiting the interaction between menin and mixed-lineage leukemia (MLL) fusion proteins.
Menin binds to the N-terminal fragment of MLL retained in all MLL fusion proteins, and the fusion proteins require menin for leukemogenic activity.
That’s why Jolanta Grembecka, PhD, and Tomasz Cierpicki, PhD, both of the University of Michigan in Ann Arbor, have been working for several years to identify small-molecule inhibitors that would block the MLL-menin interaction.
“The MLL-menin interaction is a good drug target because it’s the primary driver in [MLL] leukemia,” Dr Grembecka said. “By blocking this interaction, it’s very likely to stop the cancer.”
With that in mind, Dr Grembecka and her colleagues tested 2 compounds they developed, MI-463 and MI-503, in cell lines and mice with MLL leukemia. The compounds blocked the MLL-menin interaction without affecting normal hematopoiesis.
The team also noted that both compounds demonstrated metabolic stability and favorable pharmacokinetic profiles.
“Against all odds, we decided to explore finding a way to block the MLL-menin interaction with small molecules,” Dr Cierpicki said. “From nothing, we have been able to identify and greatly improve a compound and show that it’s got valuable potential in blocking MLL fusion leukemia in animal models.”
In a separate study published in Nature Medicine, the researchers discovered that menin and MLL play a role in androgen receptor signaling, a key driver of prostate cancer.
The team found that MI-503 and MI-136, another inhibitor of the menin-MLL interaction, were both active against castration-resistant prostate cancer in vitro and in vivo.
The researchers said they will continue to investigate the role of MLL in castration-resistant prostate cancer. And they plan to further refine their inhibitors and put the compounds through more advanced preclinical testing in MLL leukemia.
