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
  • 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. [email protected].
  • 5. College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China. [email protected].
  • 6. College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China. [email protected].
  • # 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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