2. Academic Validation
  3. Discovery of a new class of valosine containing protein (VCP/P97) inhibitors for the treatment of colorectal cancer

Discovery of a new class of valosine containing protein (VCP/P97) inhibitors for the treatment of colorectal cancer

  • Bioorg Med Chem. 2022 Nov 15:74:117050. doi: 10.1016/j.bmc.2022.117050.
Xueyuan Wang 1,  Tiantian Wen 1,  Hang Miao 2,  Wenjiao Hu 1,  Meng Lei 3,  Yongqiang Zhu 4
Affiliations

Affiliations

  • 1 College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210037, PR China.
  • 2 College of Science, Nanjing Forestry University, No. 159 Longpan Road, Nanjing 210037, PR China.
  • 3 College of Science, Nanjing Forestry University, No. 159 Longpan Road, Nanjing 210037, PR China; Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd, No. 9 Weidi Road, Nanjing 210046, PR China. Electronic address: hk-lm@163.com.
  • 4 College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210037, PR China; Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd, No. 9 Weidi Road, Nanjing 210046, PR China. Electronic address: zhyqscu@hotmail.com.
PMID: 36228523 DOI: 10.1016/j.bmc.2022.117050
Abstract

Colorectal Cancer (CRC) is a common digestive tract malignant tumor and is the third cancer-related death worldwide. Valosine containing protein (VCP/p97) is a member of the AAA ATPase family, plays an important role in the ubiquitin-mediated degradation of misfolded proteins. Studies have shown that p97 is overexpressed in colorectal Cancer and is a potential therapeutic target. Herein, a series of novel p97 inhibitors were designed, synthesized and biologically assayed. Based on the enzymatic results, structure-activity relationships (SAR) were discussed in detail. Some potent compounds were further evaluated to inhibit the proliferation of CRC cell lines HCT-116. The results showed that some compounds were active against CRC cell lines with IC50 values of less than 1 μM. Among the screened compounds, compound 10 exhibited good microsomal stabilities, pharmacokinetic properties and displayed strong antiproliferative activity against the HCT-116 cell line (0.4 μM). Furthermore, compound 10 exhibited strong in vivo Anticancer efficacy in the human CRC (HCT-116) mouse xenograft model.

Keywords

Colorectal cancer; In vivo antitumor activity; Pharmacokinetic; Structure-activity relationships; Valosine containing protein.

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