Scientists develop first drug-like compounds to inhibit elusive cancer-
linked enzymes

Date:
August 31, 2020
Source:
Michigan Medicine - University of Michigan
Summary:
Structural biology techniques helped researchers target the
nuclear receptor-binding SET domain family for the first time;
its malfunction is associated with several types of cancer.



FULL STORY ==========================================================================
A team of scientists from the University of Michigan Rogel Cancer Center
has 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 enzymes -- known as 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.

The research team -- led by Tomasz Cierpicki, Ph.D., and Jolanta
Grembecka, Ph.D. -- 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 findings published
in Nature Chemical Biology.

The team's lead compound -- known as 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."

========================================================================== Story Source: Materials provided by
Michigan_Medicine_-_University_of_Michigan. Original written by Ian
Demsky. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Huang Huang, Christina A. Howard, Sergei Zari, Hyo Je Cho, Shirish
Shukla, Hao Li, Juliano Ndoj, Paula Gonza'lez-Alonso,
Caroline Nikolaidis, Joshua Abbott, David S. Rogawski, Mykhaylo
A. Potopnyk, Katarzyna Kempinska, Hongzhi Miao, Trupta Purohit,
Andrew Henderson, Anna Mapp, Maria Luisa Sulis, Adolfo Ferrando,
Jolanta Grembecka, Tomasz Cierpicki. Covalent inhibition of NSD1
histone methyltransferase. Nature Chemical Biology, 2020; DOI:
10.1038/s41589-020-0626-6 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200831154403.htm

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