A novel non-competitive p97/VCP inhibitor induces apoptosis and autophagy to suppress colorectal cancer growth

  • Eur J Med Chem. 2026 Oct 5:315:118986. doi: 10.1016/j.ejmech.2026.118986.
Yixin Li  1 ,  Xuxiang Wen  1 ,  Ruoxuan Liu  1 ,  Lulu Wang  1 ,  Qiqi Feng  1 ,  Yaonan Wang  1 ,  Shurui Zhao  1 ,  Ming Zhao  2 ,  Xiaoyi Zhang  3
Affiliations
  • 1. Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Capital Medical University, Beijing, 100069, China; Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Capital Medical University, Beijing, 100069, China.
  • 2. Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Capital Medical University, Beijing, 100069, China; Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Capital Medical University, Beijing, 100069, China. Electronic address: [email protected].
  • 3. Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Capital Medical University, Beijing, 100069, China; Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Capital Medical University, Beijing, 100069, China. Electronic address: [email protected].
PMID: 42190433 DOI: 10.1016/j.ejmech.2026.118986
Abstract

The AAA + ATPase p97/VCP is a central regulator of protein homeostasis and has emerged as an attractive Anticancer target. However, first-generation ATP-competitive inhibitors have faced clinical setbacks due to off-target toxicity and sensitivity to ATP concentrations. Herein, we report the design, synthesis, and systematic structure-activity relationship (SAR) study of a novel series of diphenylmethyl-based non-competitive p97/VCP inhibitors derived from the allosteric hit MSC1094308. SAR optimization revealed that conversion of the amide linker to a secondary amine, coupled with the introduction of a tetrahydropyrido[3,4-b]indole scaffold and fluorine substitution on the biphenylmethyl group, dramatically enhanced p97/VCP inhibitory activity. The lead compounds, 10a and 10b, exhibited potent non-competitive inhibition (IC50 = 1.04 μM and 17 nM, respectively) and maintained efficacy independent of ATP concentration. Microscale thermophoresis (MST) confirmed strong binding affinity of 10a to p97/VCP (Kd = 14.99 μM), and limited proteolysis-mass spectrometry (LiP-MS) identified p97/VCP as a direct cellular targ et of 10a. Mechanistically, 10a induced mitochondrial membrane depolarization, leading to concurrent regulation of both apoptotic (Caspase-3, PARP cleavage) and autophagic (LC3-II, p62) pathways. In vitro, 10a demonstrated broad-spectrum antiproliferative activity across multiple Cancer cell lines and completely suppressed the growth of patient-derived colorectal Cancer organoids. In an MC38 colorectal Cancer xenograft mouse model, 10a achieved 55% tumor growth inhibition with manageable toxicity. Collectively, this study identifies 10a as a promising lead compound for colorectal Cancer therapy and establishes allosteric p97/VCP inhibition via mitochondrial stress as a viable therapeutic strategy.

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