2. Academic Validation
  3. FDW028, a novel FUT8 inhibitor, impels lysosomal proteolysis of B7-H3 via chaperone-mediated autophagy pathway and exhibits potent efficacy against metastatic colorectal cancer

FDW028, a novel FUT8 inhibitor, impels lysosomal proteolysis of B7-H3 via chaperone-mediated autophagy pathway and exhibits potent efficacy against metastatic colorectal cancer

  • Cell Death Dis. 2023 Aug 3;14(8):495. doi: 10.1038/s41419-023-06027-0.
Mengmeng Wang # 1 2,  Zhoudong Zhang # 1,  Mengxi Chen # 1,  Yixin Lv 1,  Sheng Tian 1,  Fanyi Meng 1,  Yawen Zhang 1,  Xuqin Guo 1,  Yinshuang Chen 1,  Man Yang 1,  Jiawei Li 1,  Tian Qiu 1,  Fang Xu 1,  Zhi Li 1,  Qi Zhang 1,  Jie Yang 3,  Jing Sun 3,  Hongjian Zhang 1,  Haiyang Zhang 4,  Huanqiu Li 5,  Weipeng Wang 6
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
  • 2 Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215123, China.
  • 3 Institute of Medical Technology, Suzhou Vocational Health College, Suzhou, 215009, China.
  • 4 College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China. hyzhang2020@suda.edu.cn.
  • 5 College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China. huanqiuli@suda.edu.cn.
  • 6 College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China. wangweipeng@suda.edu.cn.
  • # Contributed equally.
PMID: 37537172 DOI: 10.1038/s41419-023-06027-0
Abstract

Metastatic colorectal Cancer (mCRC) is a major cause of cancer-related mortality due to the absence of effective therapeutics. Thus, it is urgent to discover new drugs for mCRC. Fucosyltransferase 8 (FUT8) is a potential therapeutic target with high level in most malignant cancers including CRC. FUT8 mediates the core fucosylation of CD276 (B7-H3), a key immune checkpoint molecule (ICM), in CRC. FUT8-silence-induced defucosylation at N104 on B7-H3 attracts heat shock protein family A member 8 (HSPA8, also known as HSC70) to bind with 106-110 SLRLQ motif and consequently propels lysosomal proteolysis of B7-H3 through the chaperone-mediated Autophagy (CMA) pathway. Then we report the development and characterization of a potent and highly selective small-molecule inhibitor of FUT8, named FDW028, which evidently prolongs the survival of mice with CRC pulmonary metastases (CRPM). FDW028 exhibits potent anti-tumor activity by defucosylation and impelling lysosomal degradation of B7-H3 through the CMA pathway. Taken together, FUT8 inhibition destabilizes B7-H3 through CMA-mediated lysosomal proteolysis, and FDW028 acts as a potent therapeutic candidate against mCRC by targeting FUT8. FDW028, an inhibitor specifically targeted FUT8, promotes defucosylation and consequent HSC70/LAMP2A-mediated lysosomal degradation of B7-H3, and exhibits potent anti-mCRC activities.

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