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Chaperone-Mediated Autophagy-Directed Degradation of PI3K in Tumor Cells: Development of Multifunctional Peptide-Drug

Chenyu Zhang1, Honglan Zhong1, Xiang Li1,2

  • 1State Key Laboratory of Respiratory Disease, Guangzhou Key Laboratory of Tuberculosis Research, Department of Pharmacy, Guangzhou Chest Hospital, Institute of Tuberculosis, Guangzhou Medical University, Guangzhou, China.

Archiv Der Pharmazie
|July 3, 2026
PubMed

Insights

New peptide-drug conjugates precisely target and degrade cancer-driving phosphatidylinositol 3-kinase (PI3K) via chaperone-mediated autophagy (CMA). This approach shows promise for effective cancer therapy with reduced toxicity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Development

Background:

  • The phosphatidylinositol 3-kinase (PI3K) pathway is crucial in cancer, but current inhibitors face challenges with selectivity and resistance.
  • Developing targeted therapies that overcome these limitations is essential for improving cancer treatment outcomes.

Purpose of the Study:

  • To design and evaluate novel multifunctional peptide-drug conjugates (PDCs) for precise PI3K targeting and degradation using chaperone-mediated autophagy (CMA).
  • To assess the efficacy and safety of a lead PDC, TCCC-1, in preclinical cancer models.

Main Methods:

  • Development of CC-3, a PI3K inhibitor derivative with a CMA-recognition motif, followed by enhancement into TCCC-1 with tumor-homing and cell-penetrating peptides.
  • In vitro evaluation of TCCC-1 in non-small cell lung cancer (NSCLC) cells, assessing PI3K degradation, pAkt signaling, apoptosis, and cell cycle arrest.
  • In vivo efficacy and toxicity studies of TCCC-1 in NCI-H460 xenograft models.

Main Results:

  • TCCC-1 effectively degraded PI3K, inhibited pAkt signaling, and induced apoptosis and G2/M cell cycle arrest in NSCLC cells, including Copanlisib-resistant lines.
  • In vivo studies showed TCCC-1 achieved significant tumor suppression (up to 97.0%) in NCI-H460 xenografts.
  • TCCC-1 demonstrated minimal systemic toxicity, organ damage, or metabolic disturbances compared to Copanlisib.

Conclusions:

  • TCCC-1, a novel PDC utilizing CMA, offers precise PI3K degradation with enhanced tumor penetration and selectivity.
  • This approach presents a promising therapeutic strategy for cancers with hyperactivated PI3K signaling, potentially overcoming resistance and reducing systemic toxicity.
Keywords:
PI3K degradationchaperone‐mediated autophagy (CMA)non‐small cell lung cancer (NSCLC)peptide‐drug conjugates (PDCs)tumor targeting

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