2. Academic Validation
  3. Discovery of a Highly Potent and Selective Inhibitor Targeting Protein Lysine Methyltransferase NSD2

Discovery of a Highly Potent and Selective Inhibitor Targeting Protein Lysine Methyltransferase NSD2

  • J Med Chem. 2024 Sep 26;67(18):16056-16071. doi: 10.1021/acs.jmedchem.4c00639.
Jianwei Wei 1,  Qiongyu Shi 2,  Bang Li 1,  Hong Yang 2,  Li Liu 1,  Ruilin Zhou 2 3,  Zongbo Feng 1,  Zhenjiao Yang 1,  Jinhong Zhan 1,  Xiao-Feng Xiong 1 4,  Xun Huang 2 5,  Yuanxiang Wang 1 4
Affiliations

Affiliations

  • 1 Balance-Based Drug Discovery Laboratory, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
  • 2 Lingang Laboratory, Shanghai 200031, China.
  • 3 School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China.
  • 4 State Key Laboratory of Anti-Infective Drug Development, Guangzhou 510006, China.
  • 5 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
PMID: 39230932 DOI: 10.1021/acs.jmedchem.4c00639
Abstract

The histone lysine methyltransferase NSD2 has been recognized as an attractive target for Cancer treatment, due to the functional implication of its dysregulation in the initiation and progression of many cancers. Although considerable efforts have been made to develop NSD2 small-molecule inhibitors, highly potent and selective ones are still rarely available till now. Here, we report the discovery of a series of novel NSD2 inhibitors via an extensive SAR exploration of the privileged quinazoline scaffold within compound 8. The most promising compound 42 showed excellent NSD2 enzymatic inhibitory activity and good antiproliferative activity in cells. In addition, it demonstrated favorable pharmacokinetic properties and significantly inhibited the tumor growth in a RS411 tumor xenograft model with good safety. Taken together, compound 42 could be a promising NSD2 inhibitor and deserves further investigation.

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