2. Academic Validation
  3. Discovery of LLC0424 as a Potent and Selective in Vivo NSD2 PROTAC Degrader

Discovery of LLC0424 as a Potent and Selective in Vivo NSD2 PROTAC Degrader

  • J Med Chem. 2024 May 9;67(9):6938-6951. doi: 10.1021/acs.jmedchem.3c01765.
Lianchao Liu 1,  Abhijit Parolia 2 3 4 5,  Yihan Liu 2 6,  Caiyun Hou 7,  Tongchen He 2,  Yuanyuan Qiao 2 3,  Sanjana Eyunni 2 3 8,  Jie Luo 2 3,  Chungen Li 1,  Yongxing Wang 9,  Fengtao Zhou 7,  Weixue Huang 1,  Xiaomei Ren 1,  Zhen Wang 1,  Arul M Chinnaiyan 2 3 4 5 10,  Ke Ding 1 7 11
Affiliations

Affiliations

  • 1 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, no. 345 Lingling Road., Shanghai 200032, People's Republic of China.
  • 2 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 3 Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 4 Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 5 Department of Urology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 6 Cancer Biology Program, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 7 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 855 Xingye Avenue East, Guangzhou 511400, People's Republic of China.
  • 8 Molecular and Cellular Pathology Program, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 9 Livzon Research Institute, Livzon Pharmaceutical Group Inc., no. 38 Chuangye North Road, Jinwan District, Zhuhai 519000, China.
  • 10 Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 11 Hangzhou Institute of Medicine (HlM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.
PMID: 38687638 DOI: 10.1021/acs.jmedchem.3c01765
Abstract

Nuclear receptor-binding SET domain-containing 2 (NSD2), a methyltransferase that primarily installs the dimethyl MARK on lysine 36 of histone 3 (H3K36me2), has been recognized as a promising therapeutic target against Cancer. However, existing NSD2 inhibitors suffer from low activity or inferior selectivity, and none of them can simultaneously remove the methyltransferase activity and chromatin binding function of NSD2. Herein we report the discovery of a novel NSD2 degrader LLC0424 by leveraging the proteolysis-targeting chimera technology. LLC0424 potently degraded NSD2 protein with a DC50 value of 20 nM and a Dmax value of 96% in acute lymphoblastic leukemia (ALL) RPMI-8402 cells. Mechanistic studies revealed LLC0424 to selectively induce NSD2 degradation in a cereblon- and proteasome-dependent fashion. LLC0424 also caused continuous downregulation of H3K36me2 and growth inhibition of ALL cell lines with NSD2 mutation. Importantly, intravenous or intraperitoneal injection of LLC0424 showed potent NSD2 degradation in vivo.

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