7VLN

NSD2-PWWP1 domain bound with an imidazol-5-yl benzonitrile compound

Summary for 7VLN

• Entry DOI: 10.2210/pdb7vln/pdb
• Descriptor: Histone-lysine N-methyltransferase NSD2, 4-[5-[4-(aminomethyl)-2,6-dimethoxy-phenyl]-3-methyl-imidazol-4-yl]benzenecarbonitrile (2 entities in total)
• Functional Keywords: histone-lysine n-methyltransferase nsd2, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 45772.91

Authors

Cao, D.Y.,Li, Y.L.,Li, J.,Xiong, B. (deposition date: 2021-10-05, release date: 2022-07-06, Last modification date: 2023-11-29)

Primary citation

Li, N.,Yang, H.,Liu, K.,Zhou, L.,Huang, Y.,Cao, D.,Li, Y.,Sun, Y.,Yu, A.,Du, Z.,Yu, F.,Zhang, Y.,Wang, B.,Geng, M.,Li, J.,Xiong, B.,Xu, S.,Huang, X.,Liu, T.
Structure-Based Discovery of a Series of NSD2-PWWP1 Inhibitors.
J.Med.Chem., 65:9459-9477, 2022

PubMed Abstract: Overexpression, point mutations, or translocations of protein lysine methyltransferase NSD2 occur in many types of cancer cells. Therefore, it was recognized as onco-protein and considered as a promising anticancer drug target. NSD2 consists of multiple domains including a SET catalytic domain and two PWWP domains binding to methylated histone proteins. Here, we reported our efforts to develop a series of NSD2-PWWP1 inhibitors, and further structure-based optimization resulted in a potent inhibitor , which has high selectivity toward the NSD2-PWWP1 domain. The detailed biological evaluation revealed that compound can bind to NSD2-PWWP1 and then affect the expression of genes regulated by NSD2. The current discovery will provide a useful chemical probe to the future research in understanding the specific regulation mode of NSD2 by PWWP1 recognition and pave the way to develop potential drugs targeting NSD2 protein.

PubMed: 35704853
DOI: 10.1021/acs.jmedchem.2c00709

Experimental method

X-RAY DIFFRACTION (3.09 Å)