University of Michigan Researchers to Develop Potent Small Molecule Inhibitors for Cancer Treatment

Release Date: 22-Nov-2020

Researchers from one of the elite universities are focused towards development of first drug compounds that is capable of inhibiting a group of enzymes which is associated with different types of cancers such as childhood leukemia. As per the researchers who are involved in the clinical research study have observed that nuclear receptor-binding SET domain family of histone methyltransferase which is focused as an attractive drug target. To continue the clinical research study, the researchers used several different techniques such as X-ray crystallography and nuclear magnetic resonance to develop first-in-class inhibitors of a key protein known as NSD1.


It is observed that the SET domain of histone methyltransferase family is bound to number of cancers as per discussed above such as leukemia with NUP98-NSD1 translocation.  For the treatment of cancer, NSD proteins represent themselves as attractive drug targets, whereas their catalytic side exist in auto-inhibited conformation, thereby presenting some of the important and notable challenges for inhibitor development.


The researchers in the respective clinical trial study used a fragment-based screening strategy which was further followed by chemical optimization. The overall procedure resulted in the development of the first-in-class irreversible small molecule inhibitors of SET domain protein 1. The crystal structure developed by the researchers of NSD1 when covalently bound revealed that a conformational change in the autoinhibitory loop of the SET domain and formation of a channel-like pocket suitable for targeting with small molecule. The lead compound developed by the researchers demonstrated on target activity in NUP98-NSD1 leukemia cells. Also, it led to inhibition of histone H3 lysine 36 dimethylation and downregulation of target genes, and impaired colony formation in an NUP98-NSD1 patient sample. The clinical research study is estimated to take inhibitors of the NSD histone methyltransferases to a completely novel ally in cancer therapeutics market.


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