2. Academic Validation
  3. Development of PI3K/mTOR-HSP90 ligand conjugates for improved colorectal cancer therapy

Development of PI3K/mTOR-HSP90 ligand conjugates for improved colorectal cancer therapy

  • Eur J Med Chem. 2026 Jan 15;302(Pt 2):118286. doi: 10.1016/j.ejmech.2025.118286.
Zhengyang Wang 1,  Xiaoyuan Hua 1,  Chuchu Li 1,  Hong-Xia Dai 2,  Yanzhi Guo 1,  Wanjing Zeng 1,  Xu-Wen Li 3,  Suzhen Dong 4,  Mingliang Ma 5
Affiliations

Affiliations

  • 1 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China.
  • 2 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, Chinae.
  • 3 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, Chinae; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: [email protected].
  • 4 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China. Electronic address: [email protected].
  • 5 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China; Key Laboratory of Brain Functional Genomics, Ministry of Education, School of Life Science, East China Normal University, Shanghai, 200062, China. Electronic address: [email protected].
PMID: 41176892 DOI: 10.1016/j.ejmech.2025.118286
Abstract

Dysregulation of the PI3K/Akt/mTOR signaling pathway is a hallmark in colorectal Cancer (CRC) development, making it an important target for Anticancer drug discovery. However, limited efficacy and poor selectivity have significantly hindered the clinical application of PI3K/mTOR inhibitors. To overcome these limitations, we designed a series of novel small-molecule drug conjugates (SMDCs) by linking potent PI3K/mTOR inhibitors to extracellular heat shock protein 90 (eHSP90)-targeting ligands via cleavable linkers. This strategy exploits the overexpression of eHSP90 in tumors to facilitate receptor-mediated endocytosis and selective intracellular release of the active payload within the tumor microenvironment. Among the synthesized conjugates, CC-11 emerged as a lead compound with potent HSP90 binding activity (IC50 = 15 nM) and inhibition of PI3Kα kinase (IC50 = 0.54 nM). CC-11 demonstrated superior in vitro anti-proliferative activity against CRC cell lines (HCT-116 IC50 = 0.20 μM; HT-29 IC50 = 0.89 μM) while exhibiting enhanced selectivity (50-fold) over normal liver cells compared to its monomeric PI3K Inhibitor counterpart (CC-M-1). Gene knockdown experiments confirmed that CC-11's activity is dependent on the presence of HSP90. Importantly, CC-11 achieved significantly improved in vivo efficacy in HCT-116 xenograft models (62.12 % tumor growth inhibition) compared to CC-M-1 (32.95 %), without observable toxicity. Mechanistic studies validated target engagement through suppression of the PI3K/mTOR signaling pathway. Although further optimization of plasma stability is required, this work highlights the potential of SMDCs utilizing HSP90 ligands to enhance both the selectivity and efficacy of PI3K/mTOR inhibitors, positioning CC-11 as a promising candidate for targeted CRC therapy.

Keywords

Colorectal cancer; HSP90; PI3K/mTOR; SMDC.

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