2. Academic Validation
  3. Natural products as payloads for antibody-drug conjugates: Cyclopamine linked to cetuximab for hedgehog pathway inhibition

Natural products as payloads for antibody-drug conjugates: Cyclopamine linked to cetuximab for hedgehog pathway inhibition

  • Bioorg Chem. 2026 Feb:169:109452. doi: 10.1016/j.bioorg.2025.109452.
Giovanni Ricciardella 1,  Francesca Migliorini 1,  Luisa Maresca 2,  Elena Cini 1,  Giovanni Ievoli 1,  Elena Petricci 3,  Maurizio Taddei 4,  Demetra Zambardino 1,  Barbara Stecca 5,  Alberto Montalbano 6,  Enrica Crivaro 5
Affiliations

Affiliations

  • 1 Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Via A. Moro 2, 53100 Siena, Italy.
  • 2 Core Research Laboratory - Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Viale Pieraccini 6, 50139 Firenze, Italy; Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Italy.
  • 3 Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Via A. Moro 2, 53100 Siena, Italy. Electronic address: elena.petricci@unisi.it.
  • 4 Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Via A. Moro 2, 53100 Siena, Italy. Electronic address: maurizio.taddei@unisi.it.
  • 5 Core Research Laboratory - Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Viale Pieraccini 6, 50139 Firenze, Italy.
  • 6 Dipartimento di Medicina Sperimentale e Clinica (DMSC), Università di Firenze, Viale Pieraccini 6, 50139 Firenze, Italy.
PMID: 41485443 DOI: 10.1016/j.bioorg.2025.109452
Abstract

Cyclopamine, a natural product that enabled the identification of Smoothened as a central regulator of the Hedgehog (HH) signalling pathway, has never advanced to clinical testing due to unfavourable pharmacokinetics and multiple off-target effects. In this study, we describe two novel antibody-drug conjugates (ADCs) in which Cetuximab is covalently linked to cyclopamine, to selectively deliver this natural product into melanoma cells exhibiting HH pathway activation and epidermal growth factor receptor (EGFR) expression. The ADC, which contains an acid-cleavable linker, effectively inhibited GLI1 and GLI2 expression and demonstrated antiproliferative activity in melanoma cell lines A375 and SK-MEL-5, highlighting the efficacy of cyclopamine and monoclonal antibody (mAb) conjugation. This activity was associated with a pro-apoptotic effect directly linked to HH pathway inhibition. The linker-payload system was stable in plasma yet released gradually cyclopamine at pH 5.5. These results suggest the feasibility of using natural products as payloads for the construction of ADCs to inhibit HH signalling in Cancer cells.

Keywords

Antibody-drug conjugate; Click chemistry; Hedgehog signalling pathway; Natural products.

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