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Updated: Jan 20, 2026

Biotinylated Cell-penetrating Peptides to Study Intracellular Protein-protein Interactions
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Biotinylated Cell-penetrating Peptides to Study Intracellular Protein-protein Interactions

Published on: December 20, 2017

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Exploiting intracellular oncogenic proteins to release cytotoxins

Matthias Schild1, Dennis Gillingham1

  • 1Department of Chemistry, University of Basel 4056 Basel Switzerland dennis.gillingham@unibas.ch.

RSC Medicinal Chemistry
|January 19, 2026
PubMed

Insights

Small molecule inhibitors are repurposed for targeted intracellular drug delivery. This strategy uses inhibitor-tetrazine conjugates to activate TCO-caged prodrugs, enabling controlled release of cytotoxic payloads for cancer therapy.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • Antibody-drug conjugates highlight targeted cytotoxic delivery, but many oncogenic drivers are intracellular and inaccessible to antibodies.
  • Small molecule inhibitors are currently used for intracellular targets but lack targeted delivery mechanisms.
  • Developing novel strategies for targeted intracellular delivery of cytotoxic payloads is crucial for advancing cancer therapy.

Purpose of the Study:

  • To explore repurposing small molecule inhibitors for intracellular delivery and controlled release of cytotoxic payloads.
  • To develop a pre-targeting strategy using click-to-release chemistry for selective activation of caged prodrugs.
  • To demonstrate the feasibility of this approach using an epidermal growth factor receptor (EGFR) targeted therapy.

Main Methods:

  • Utilized click-to-release chemistry to create inhibitor-tetrazine conjugates for targeted activation.
  • Developed systemically administered *trans*-cyclooctene (TCO) caged prodrugs for controlled payload release.
  • Employed an afatinib-tetrazine conjugate to target EGFR-overexpressing cells and deliver a monomethyl auristatin E (MMAE) payload.

Main Results:

  • Achieved sufficient intracellular retention of the afatinib-tetrazine conjugate in EGFR-overexpressing cells.
  • Demonstrated successful toxicity recovery from a TCO-protected MMAE derivative upon intracellular activation.
  • Validated the concept of targeted intracellular delivery and controlled release of cytotoxic payloads.

Conclusions:

  • Repurposing small molecule inhibitors with click-to-release chemistry enables targeted intracellular delivery of cytotoxic payloads.
  • This strategy allows for controlled payload release, overcoming limitations of traditional antibody-drug conjugates for intracellular targets.
  • Establishes a foundation for expanding targeted drug delivery to previously inaccessible oncogenic drivers, improving cancer treatment efficacy.

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