-transparent.png){kind=logo}
Discovery of a Potent and Selective Targeted NSD2 Degrader for the Reduction of H3K36me2. 2023
Ronan P Hanley, and
David Y Nie, and
John R Tabor, and
Fengling Li, and
Amin Sobh, and
Chenxi Xu, and
Natalie K Barker, and
David Dilworth, and
Taraneh Hajian, and
Elisa Gibson, and
Magdalena M Szewczyk, and
Peter J Brown, and
Dalia Barsyte-Lovejoy, and
Laura E Herring, and
Gang Greg Wang, and
Jonathan D Licht, and
Masoud Vedadi, and
Cheryl H Arrowsmith, and
Lindsey I James
Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
Nuclear receptor-binding SET domain-containing 2 (NSD2) plays important roles in gene regulation, largely through its ability to dimethylate lysine 36 of histone 3 (H3K36me2). Despite aberrant activity of NSD2 reported in numerous cancers, efforts to selectively inhibit the catalytic activity of this protein with small molecules have been unsuccessful to date. Here, we report the development of UNC8153, a novel NSD2-targeted degrader that potently and selectively reduces the cellular levels of both NSD2 protein and the H3K36me2 chromatin mark. UNC8153 contains a simple warhead that confers proteasome-dependent degradation of NSD2 through a novel mechanism. Importantly, UNC8153-mediated reduction of H3K36me2 through the degradation of NSD2 results in the downregulation of pathological phenotypes in multiple myeloma cells including mild antiproliferative effects in MM1.S cells containing an activating point mutation and antiadhesive effects in KMS11 cells harboring the t(4;14) translocation that upregulates NSD2 expression.
Related Publications
Ronan P Hanley, and
David Y Nie, and
John R Tabor, and
Fengling Li, and
Amin Sobh, and
Chenxi Xu, and
Natalie K Barker, and
David Dilworth, and
Taraneh Hajian, and
Elisa Gibson, and
Magdalena M Szewczyk, and
Peter J Brown, and
Dalia Barsyte-Lovejoy, and
Laura E Herring, and
Gang Greg Wang, and
Jonathan D Licht, and
Masoud Vedadi, and
Cheryl H Arrowsmith, and
Lindsey I James
April 2024,
Journal of medicinal chemistry,
Ronan P Hanley, and
David Y Nie, and
John R Tabor, and
Fengling Li, and
Amin Sobh, and
Chenxi Xu, and
Natalie K Barker, and
David Dilworth, and
Taraneh Hajian, and
Elisa Gibson, and
Magdalena M Szewczyk, and
Peter J Brown, and
Dalia Barsyte-Lovejoy, and
Laura E Herring, and
Gang Greg Wang, and
Jonathan D Licht, and
Masoud Vedadi, and
Cheryl H Arrowsmith, and
Lindsey I James
August 2022,
Angewandte Chemie (International ed. in English),
Ronan P Hanley, and
David Y Nie, and
John R Tabor, and
Fengling Li, and
Amin Sobh, and
Chenxi Xu, and
Natalie K Barker, and
David Dilworth, and
Taraneh Hajian, and
Elisa Gibson, and
Magdalena M Szewczyk, and
Peter J Brown, and
Dalia Barsyte-Lovejoy, and
Laura E Herring, and
Gang Greg Wang, and
Jonathan D Licht, and
Masoud Vedadi, and
Cheryl H Arrowsmith, and
Lindsey I James
August 2022,
Journal of medicinal chemistry,
Ronan P Hanley, and
David Y Nie, and
John R Tabor, and
Fengling Li, and
Amin Sobh, and
Chenxi Xu, and
Natalie K Barker, and
David Dilworth, and
Taraneh Hajian, and
Elisa Gibson, and
Magdalena M Szewczyk, and
Peter J Brown, and
Dalia Barsyte-Lovejoy, and
Laura E Herring, and
Gang Greg Wang, and
Jonathan D Licht, and
Masoud Vedadi, and
Cheryl H Arrowsmith, and
Lindsey I James
December 2020,
Journal of medicinal chemistry,
Ronan P Hanley, and
David Y Nie, and
John R Tabor, and
Fengling Li, and
Amin Sobh, and
Chenxi Xu, and
Natalie K Barker, and
David Dilworth, and
Taraneh Hajian, and
Elisa Gibson, and
Magdalena M Szewczyk, and
Peter J Brown, and
Dalia Barsyte-Lovejoy, and
Laura E Herring, and
Gang Greg Wang, and
Jonathan D Licht, and
Masoud Vedadi, and
Cheryl H Arrowsmith, and
Lindsey I James
June 2024,
Bioorganic & medicinal chemistry letters,
Ronan P Hanley, and
David Y Nie, and
John R Tabor, and
Fengling Li, and
Amin Sobh, and
Chenxi Xu, and
Natalie K Barker, and
David Dilworth, and
Taraneh Hajian, and
Elisa Gibson, and
Magdalena M Szewczyk, and
Peter J Brown, and
Dalia Barsyte-Lovejoy, and
Laura E Herring, and
Gang Greg Wang, and
Jonathan D Licht, and
Masoud Vedadi, and
Cheryl H Arrowsmith, and
Lindsey I James
February 2023,
Journal of medicinal chemistry,
Ronan P Hanley, and
David Y Nie, and
John R Tabor, and
Fengling Li, and
Amin Sobh, and
Chenxi Xu, and
Natalie K Barker, and
David Dilworth, and
Taraneh Hajian, and
Elisa Gibson, and
Magdalena M Szewczyk, and
Peter J Brown, and
Dalia Barsyte-Lovejoy, and
Laura E Herring, and
Gang Greg Wang, and
Jonathan D Licht, and
Masoud Vedadi, and
Cheryl H Arrowsmith, and
Lindsey I James
September 2022,
European journal of medicinal chemistry,
Ronan P Hanley, and
David Y Nie, and
John R Tabor, and
Fengling Li, and
Amin Sobh, and
Chenxi Xu, and
Natalie K Barker, and
David Dilworth, and
Taraneh Hajian, and
Elisa Gibson, and
Magdalena M Szewczyk, and
Peter J Brown, and
Dalia Barsyte-Lovejoy, and
Laura E Herring, and
Gang Greg Wang, and
Jonathan D Licht, and
Masoud Vedadi, and
Cheryl H Arrowsmith, and
Lindsey I James
January 2023,
Bioorganic & medicinal chemistry letters,
Ronan P Hanley, and
David Y Nie, and
John R Tabor, and
Fengling Li, and
Amin Sobh, and
Chenxi Xu, and
Natalie K Barker, and
David Dilworth, and
Taraneh Hajian, and
Elisa Gibson, and
Magdalena M Szewczyk, and
Peter J Brown, and
Dalia Barsyte-Lovejoy, and
Laura E Herring, and
Gang Greg Wang, and
Jonathan D Licht, and
Masoud Vedadi, and
Cheryl H Arrowsmith, and
Lindsey I James
January 2019,
Journal of cellular and molecular medicine,
Ronan P Hanley, and
David Y Nie, and
John R Tabor, and
Fengling Li, and
Amin Sobh, and
Chenxi Xu, and
Natalie K Barker, and
David Dilworth, and
Taraneh Hajian, and
Elisa Gibson, and
Magdalena M Szewczyk, and
Peter J Brown, and
Dalia Barsyte-Lovejoy, and
Laura E Herring, and
Gang Greg Wang, and
Jonathan D Licht, and
Masoud Vedadi, and
Cheryl H Arrowsmith, and
Lindsey I James
August 2022,
European journal of medicinal chemistry,
