More Potent, Less Toxic: Scientists Develop a Better Type of Chemotherapy

, have discovered two compounds that are both more potent and less toxic than the current leukemia therapies. The molecules operate in a manner that differs from that of conventional cancer treatments and may serve as the foundation for a whole new class of drugs.

A cell’s epigenome is copied and preserved by an enzyme called DNMT1. This enzyme ensures, for example, that a dividing liver cell turns into two liver cells and not a brain cell. Unfortunately, DNMT3A’s active site is virtually identical to that of DNMT1, so the drug shuts down epigenetic regulation in all of the patient’s 30 to 40 trillion cells. This leads to one of the drug industry’s biggest bottlenecks: off-target toxicity.

Around the same time, the New England Journal of Medicine ran a deep dive into the mutations present in leukemia patients. The authors of that study discovered that the most frequent mutations in acute myeloid leukemia patients are in the DNMT3A gene. Surprisingly, Holz-Schietinger had studied the exact same mutations. The team now had a direct link between DNMT3A and the epigenetic changes leading to acute myeloid leukemia.

This achievement is no mean feat. “Developing small molecules that disrupt protein-protein interactions has proven challenging,” noted lead author Jonathan Sandoval of UC San Francisco, a former doctoral student in Reich’s lab. “These are the first reported inhibitors of DNMT3A that disrupt protein-protein interactions.”

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