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Exploring bat-inspired cyclic tryptophan diketopiperazines as ABCB1 Inhibitors

Javier Yu Peng Koh1, Yoko Itahana1, Alexander Krah2

  • 1Programme in Cancer & Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.

Communications Chemistry
|July 13, 2024
PubMed

Insights

Scientists developed a novel tryptophan-based compound, C3N-Dbn-Trp2, to overcome chemotherapy resistance by inhibiting the ABCB1 transporter. This breakthrough offers hope for treating drug-resistant cancers.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Cancer Biology

Background:

  • Chemotherapy resistance, driven by ATP binding cassette subfamily B member 1 (ABCB1) transporter overexpression, is a significant cause of cancer mortality.
  • Existing ABCB1 inhibitors have shown limited clinical success, necessitating novel therapeutic strategies.

Purpose of the Study:

  • To develop a new class of ABCB1 inhibitors based on tryptophan, inspired by bats' low cancer incidence and high ABCB1 expression.
  • To identify and synthesize a potent ABCB1 inhibitor capable of restoring chemotherapy sensitivity in resistant cancer cells.

Main Methods:

  • Molecular simulations were employed to study ABCB1-substrate interactions.
  • A benzylated Cyclo-tryptophan derivative (C3N-Dbn-Trp2) was synthesized.
  • The efficacy of C3N-Dbn-Trp2 was evaluated in drug-resistant human cancer cells.

Main Results:

  • C3N-Dbn-Trp2 demonstrated potent inhibition of ABCB1 activity, comparable or superior to verapamil.
  • The compound restored sensitivity to chemotherapy in drug-resistant cancer cells.
  • C3N-Dbn-Trp2 exhibited no adverse effects on cancer cell proliferation.

Conclusions:

  • The novel tryptophan-derived compound C3N-Dbn-Trp2 is a promising lead for developing effective ABCB1 inhibitors.
  • This approach offers a potential strategy to overcome chemotherapy resistance in various cancers.
  • Further development of C3N-Dbn-Trp2 could lead to improved cancer treatment outcomes.

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