2. Academic Validation
  3. Structural Modification and Pharmacological Evaluation of Substituted Quinoline-5,8-diones as Potent NSD2 Inhibitors

Structural Modification and Pharmacological Evaluation of Substituted Quinoline-5,8-diones as Potent NSD2 Inhibitors

  • J Med Chem. 2023 Jan 26;66(2):1634-1651. doi: 10.1021/acs.jmedchem.2c01920.
Hairong Tang 1 2,  Aisong Yu 3 4,  Li Xing 1 3,  Xiaoyu Chen 1,  Huaqian Ding 1 3,  Hong Yang 3 5,  Zilan Song 1,  Qiongyu Shi 3 5,  Meiyu Geng 3,  Xun Huang 3 5,  Ao Zhang 1 5 2
Affiliations

Affiliations

  • 1 Shanghai Frontiers Science Center for Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 2 Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 3 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5 Lingang Laboratory, Shanghai 200210,China.
PMID: 36642961 DOI: 10.1021/acs.jmedchem.2c01920
Abstract

The histone lysine methyltransferase NSD2 is overexpressed, translocated, or mutated in multiple types of cancers and has emerged as an attractive therapeutic target. However, the development of small-molecule NSD2 inhibitors is still in its infancy, and selective and efficacious NSD2 inhibitors are highly desirable. Here, in view of the structural novelty of the reported NSD2 inhibitor DA3003-1, we conducted a comprehensive structural optimization based on the quinoline-5,8-dione scaffold. Compound 15a was identified possessing both high NSD2 inhibitory activity and potent anti-proliferative effects in the cell. Meanwhile, compound 15a has an excellent pharmacokinetic profile with high oral bioavailability. Further, this compound was found to display significant antitumor efficacy with desirable safety profile in the multiple myeloma xenograft mice models, thus warranting it as a promising candidate for further investigation.

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