Professor Weipeng Wang’s group discovered a novel FUT8 inhibitor FDW028 exhibiting potent efficacy against metastatic colorectal cancer

Prof. Wang’ group published a research paper entitled “FDW028, a novel FUT8 inhibitor, impels lysosomal proteolysis of B7-H3 via chaperone-mediated autophagy pathway and exhibits potent efficacy against metastatic colorectal cancer” onCell Death & Disease(IF: 9.0) on Aug 3, 2023. Their findings demonstrate that FDW028 (Issuedpatent: ZL202210012997.7), an inhibitor selectively targets FUT8, promotes defucosylation and consequent HSC70/LAMP2A-mediated lysosomal degradation of B7-H3, and evidently prolongs the survival of mice with metastatic CRC (mCRC).

Background:

Nowadays the incidence and mortality of CRC rank the third and the second among cancers, respectively.Approximately 50% of patients with initially localized CRC will develop metastases, which are incurable with a 5-year survival typically not exceeding 10% due to the lack of effective therapeutics.Non-selective inhibitors of fucosyltransferases have shown efficacy against cancers in clinical trials, while serious adverse reactions have been observed for them.Prof. Wang’ group was invited to review on the potential therapeutic targets of fucosyltransferases(Drug Discovery Today, 2023), which focused on the FUT8-mediated regulation of immune checkpoint molecules including PD-1/PD-L1 and PD-L2, and the recent advancement of FUT8 targeted inhibitors.

Highlight 1: Defucosylation impelled lysosomal degradation of B7-H3 through CMA pathway

B7-H3 is an important immune checkpoint molecule in the same family as PD-L1. Enoblituzumab, a B7-H3-targeting antibody, showed potent clinical efficacy against prostate cancer in a Phase II clinical trial. The current study demonstrated that the core fucosylation at N104 on B7-H3 was mediated by FUT8. 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 106-110SLRLQ motif and consequently propels lysosomal proteolysis of B7-H3 through the chaperone-mediated autophagy pathway.

Highlight 2: FDW028 apparently prolonged the survival of mCRC mice

The first FUT8 targeted inhibitor FDW028 was screened out based on computer-aided drug design. FDW028 exhibited potent inhibition abilities in the proliferation and migration capacity of CRC cells bothin vitroandin vivo. FDW028 showed a comparable antitumor activity in SW480 xenografts with 5-Fu, a first-line clinical remedy for CRC. Especially, FDW028 apparently prolonged the survival of mice with CRC pulmonary metastases.

Significance:

Prof. Wang’ group revealed the roles of FUT8 and core fucosylation in the stability of B7-H3 and discovered a novel FUT8 inhibitor, FDW028, with potent anti-mCRC activities in the present study. In addition, this work provides lead compounds for the development of therapeutic drugs for mCRC.

Reference:

Wang MM, Zhang ZD, Chen MX, Lv YX, Tian S, Meng FY, et al. 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 & Disease2023, 14(8): 495.

Corresponding author:

Weipeng Wang, Ph.D., Professor, vice dean of the College of Pharmaceutical Sciences, Soochow University. He is the associate editor of Frontiers in Bioengineering and Biotechnology. His research field is anti-tumor target discovery and new drug development based on regulation of immune checkpoint molecules. He has published more than 60 SCI research papers onACS Sustainable Chemistry & Engineering, Cell Death Dis, Anal Chim Acta,et al. In addition, he has 5 issued Chinese or international patents.

Huanqiu Li, Ph.D., Associate Professor at the College of Pharmaceutical Sciences, Soochow University. His research field is design, synthesis and target identification of anti-inflammatory and anti-tumor targeted small molecule inhibitors. He has published more than 60 SCI research papers onJ Med Chem, J Adv Res, Drug Discov Today,et al.In addition, he has 12 issued Chinese patents.

Haiyang Zhang, Ph.D., Associate Professor at the College of Pharmaceutical Sciences, Soochow University. His research field is exosome isolation, cancer biomarker screening and exosome drug delivery systems. He has published more than 10 SCI research papers onAnal Chem, Green Chem, Cell Death Dis,et al.In addition, he has 5 issued Chinese patents.