2. Academic Validation
  3. Discovery of LLC355 as an Autophagy-Tethering Compound for the Degradation of Discoidin Domain Receptor 1

Discovery of LLC355 as an Autophagy-Tethering Compound for the Degradation of Discoidin Domain Receptor 1

  • J Med Chem. 2024 May 23;67(10):8043-8059. doi: 10.1021/acs.jmedchem.4c00162.
Lianchao Liu 1,  Lijie Zhao 1,  Lujun Yang 2 3,  Minxue Chai 4,  Zhengyong Liu 5,  Nan Ma 5,  Yongxing Wang 6,  Qinxue Wu 1,  Jing Guo 5,  Fengtao Zhou 5,  Weixue Huang 1,  Xiaomei Ren 1,  Jian Wang 4,  Ming Ding 7,  Zhen Wang 1,  Ke Ding 1 3 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Road, Shanghai 200032, China.
  • 2 School of Molecular Medicine, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, #1 Xiangshan Branch Lane, Hangzhou 310024, China.
  • 3 Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.
  • 4 College of Chemistry and Materials Science, Anhui Normal University, 189 South Jiuhua Road, Wuhu, Anhui 241002, China.
  • 5 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, China.
  • 6 Livzon Research Institute, Livzon Pharmaceutical Group Inc., #38 Chuangye North Road, Jinwan District, Zhuhai 519000, China.
  • 7 School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China.
PMID: 38730324 DOI: 10.1021/acs.jmedchem.4c00162
Abstract

Discoidin Domain Receptor 1 (DDR1) is a potential target for Cancer drug discovery. Although several DDR1 kinase inhibitors have been developed, recent studies have revealed the critical roles of the noncatalytic functions of DDR1 in tumor progression, metastasis, and immune exclusion. Degradation of DDR1 presents an opportunity to block its noncatalytic functions. Here, we report the discovery of the DDR1 degrader LLC355 by employing autophagosome-tethering compound technology. Compound LLC355 efficiently degraded DDR1 protein with a DC50 value of 150.8 nM in non-small cell lung Cancer NCI-H23 cells. Mechanistic studies revealed compound LLC355 to induce DDR1 degradation via lysosome-mediated Autophagy. Importantly, compound LLC355 potently suppressed Cancer cell tumorigenicity, migration, and invasion and significantly outperformed the corresponding inhibitor 1. These results underline the therapeutic advantage of targeting the noncatalytic function of DDR1 over inhibition of its kinase activity.

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