2. Academic Validation
  3. Exploring bat-inspired cyclic tryptophan diketopiperazines as ABCB1 Inhibitors

Exploring bat-inspired cyclic tryptophan diketopiperazines as ABCB1 Inhibitors

  • Commun Chem. 2024 Jul 13;7(1):158. doi: 10.1038/s42004-024-01225-z.
Javier Yu Peng Koh # 1,  Yoko Itahana # 1,  Alexander Krah # 2,  Habib Mostafa # 3,  Mingmin Ong 1,  Sahana Iwamura 4,  Dona Mariya Vincent 3,  Sabhashina Radha Krishnan 1,  Weiying Ye 1,  Pierre Wing Chi Yim 1,  Tushar M Khopade 3,  Kunihiko Chen 1,  Pui San Kong 5,  Lin-Fa Wang 5,  Roderick W Bates 6,  Yasuhisa Kimura 4,  Rajesh Viswanathan 7,  Peter J Bond 8 9,  Koji Itahana 10
Affiliations

Affiliations

  • 1 Programme in Cancer & Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.
  • 2 Bioinformatics Institute (BII), Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore.
  • 3 Department of Chemistry, Indian Institute of Science Education and Research (IISER) Tirupati, Andhra Pradesh, India.
  • 4 Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan.
  • 5 Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore.
  • 6 School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore, Singapore.
  • 7 Department of Chemistry, Indian Institute of Science Education and Research (IISER) Tirupati, Andhra Pradesh, India. rajesh@iisertirupati.ac.in.
  • 8 Bioinformatics Institute (BII), Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore. peterjb@bii.a-star.edu.sg.
  • 9 Department of Biological Sciences, National University of Singapore, Singapore, Singapore. peterjb@bii.a-star.edu.sg.
  • 10 Programme in Cancer & Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore. koji.itahana@duke-nus.edu.sg.
  • # Contributed equally.
PMID: 39003409 DOI: 10.1038/s42004-024-01225-z
Abstract

Chemotherapy-induced drug resistance remains a major cause of Cancer recurrence and patient mortality. ATP binding cassette subfamily B member 1 (ABCB1) transporter overexpression in tumors contributes to resistance, yet current ABCB1 inhibitors have been unsuccessful in clinical trials. To address this challenge, we propose a new strategy using tryptophan as a lead molecule for developing ABCB1 inhibitors. Our idea stems from our studies on bat cells, as bats have low Cancer incidences and high ABCB1 expression. We hypothesized that potential ABCB1 substrates in bats could act as competitive inhibitors in humans. By molecular simulations of ABCB1-substrate interactions, we generated a benzylated Cyclo-tryptophan (C3N-Dbn-Trp2) that inhibits ABCB1 activity with efficacy comparable to or better than the classical inhibitor, verapamil. C3N-Dbn-Trp2 restored chemotherapy sensitivity in drug-resistant human Cancer cells with no adverse effect on cell proliferation. Our unique approach presents a promising lead toward developing effective ABCB1 inhibitors to treat drug-resistant cancers.

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