Cell Death and Disease (Aug 2023)

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

  • Mengmeng Wang,
  • Zhoudong Zhang,
  • Mengxi Chen,
  • Yixin Lv,
  • Sheng Tian,
  • Fanyi Meng,
  • Yawen Zhang,
  • Xuqin Guo,
  • Yinshuang Chen,
  • Man Yang,
  • Jiawei Li,
  • Tian Qiu,
  • Fang Xu,
  • Zhi Li,
  • Qi Zhang,
  • Jie Yang,
  • Jing Sun,
  • Hongjian Zhang,
  • Haiyang Zhang,
  • Huanqiu Li,
  • Weipeng Wang

DOI
https://doi.org/10.1038/s41419-023-06027-0
Journal volume & issue
Vol. 14, no. 8
pp. 1 – 13

Abstract

Read online

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.