Researchers at the University of Michigan (U-M) Rogel Cancer Center say they have developed the first drug-like compounds to inhibit a key family of enzymes whose malfunction is associated with several types of cancer, including an aggressive form of childhood leukemia.

The nuclear receptor-binding SET domain (NSD) family of histone methyltransferases have long been an attractive drug target, but efforts to attack them have previously proved elusive because the shape of the binding sites in these enzymes makes it difficult for drug-like molecules to bind to it, report the scientists.

The team, led by Tomasz Cierpicki, PhD, and Jolanta Grembecka, PhD, used a variety of techniques, including X-ray crystallography and nuclear magnetic resonance to develop first-in-class inhibitors of a key protein known as NSD1, according to their paper “Covalent inhibition of NSD1 histone methyltransferase” in Nature Chemical Biology.

“The nuclear receptor-binding SET domain (NSD) family of histone methyltransferases is associated with various malignancies, including aggressive acute leukemia with NUP98-NSD1 translocation. While NSD proteins represent attractive drug targets, their catalytic SET domains exist in autoinhibited conformation, presenting notable challenges for inhibitor development,” write the investigators.

“Here, we employed a fragment-based screening strategy followed by chemical optimization, which resulted in the development of the first-in-class irreversible small-molecule inhibitors of the nuclear receptor-binding SET domain protein 1 (NSD1) SET domain. The crystal structure of NSD1 in complex with covalently bound ligand reveals a conformational change in the autoinhibitory loop of the SET domain and formation of a channel-like pocket suitable for targeting with small molecules.”

“Our covalent lead—compound BT5—demonstrates on-target activity in NUP98-NSD1 leukemia cells, including inhibition of histone H3 lysine 36 dimethylation and downregulation of target genes, and impaired colony formation in an NUP98-NSD1 patient sample. This study will facilitate the development of the next generation of potent and selective inhibitors of the NSD histone methyltransferases.”

The team’s lead compound (BT5) showed promising activity in leukemia cells with the NUP98-NSD1 chromosomal translocation that is seen in a subset of pediatric leukemia patients.

“Our study, which was years in the making, demonstrates that targeting this key enzyme with small-molecule inhibitors is a feasible approach,” says Cierpicki, an associate professor of biophysics and pathology at U-M. “These findings will facilitate the development of the next generation of potent and selective inhibitors of these enzymes, which are overexpressed, mutated or undergo translocations in several types of cancer.”

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