Selective TRPV2 Antagonists Derived from the Natural Product Piperlongumine Inhibit Cancer Cell Migration and Metastasis.
Overview
- Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K
- GIMM - Gulbenkian Institute for Molecular Medicine, Avenida Prof. Egas Moniz, Lisboa 1649-028, Portugal
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernandez, Avda. Universidad s/n, Elche 03202, Spain
- Chemprecise Lda, Torres Vedras 2560-247, Portugal
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon 1649-003, Portugal
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria
- Departamento de Química, Universidad de La Rioja, Instituto de Investigación en Química (IQUR), Logroño 26006, Spain
- Translational Chemical Biology Group, Spanish National Cancer Research Centre 26 (CNIO), Madrid 28029, Spain
Abstract
TRPV2 is the least studied member of the vanilloid TRP subfamily despite its emerging relevance in cancer metastasis, pain, and inflammation. Although several small-molecule TRPV2 modulators have been reported, including the natural products piperlongumine (PL) and cannabidiol, all lack selectivity, complicating the interpretation of phenotypic readouts and functional insights into the role of the channel in health and disease. Here, we report a series of PL-based derivatives rationally designed to maintain TRPV2 antagonism while eliminating covalent off-target activity associated with the electrophilic groups present in PL. Using electrophysiological and calcium fluorescence imaging assays in HEK293T cells and DRG nociceptors, we identified HKC54 as the most potent TRPV2 antagonist to date (IC50 = 0.4 μM), displaying ∼50-fold selectivity over TRPV1 and ∼70-fold selectivity over TRPA1. Cellular thermal shift assays demonstrated direct TRPV2 engagement, and molecular dynamics and docking studies suggest a near-identical binding mode of the derivatives to PL. To assess proteome-wide selectivity, we pursued an unbiased chemoproteomic strategy and developed photoaffinity probes derived from PL and noncovalent derivative HKC22. Whereas the PL-based probe labeled many established covalent and noncovalent PL targets (e.g., GSTP1, GSTO1, STAT3, and KEAP1), no off-targets were detected for HKC22, suggesting high selectivity for TRPV2. Finally, PL derivatives inhibited cancer cell migration in vitro and suppressed metastasis in vivo, underscoring the therapeutic potential of selective TRPV2 antagonists.
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structure/ , at PDB; found in the text, “Introduction”6wkn
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Version 1, 30 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 15 authors, 11 MeSH terms, 7 funders, 79 references.
Cite
This paper
Kiely-Collins, H., Tang, C., Marques, M. C., Butron, L., Lamberti, A., Bossons, N., Offensperger, F., Brennsteiner, V., Sousa, B., Carvalho, L., Ferrer-Montiel, A., Corzana, F., Winter, G. E., Fernandez-Carvajal, A., & Bernardes, G. J. L. (2026). Selective TRPV2 Antagonists Derived from the Natural Product Piperlongumine Inhibit Cancer Cell Migration and Metastasis. ACS chemical biology, 21(4), 674-688. https://
BibTeX
@article{kielycollins202
author = {Kiely-Collins, Hannah and Tang, Cong and Marques, Marta C and Butron, Laura and Lamberti, Angela and Bossons, Nicholas and Offensperger, Fabian and Brennsteiner, Vincenth and Sousa, Bárbara and Carvalho, Luís and Ferrer-Montiel, Antonio and Corzana, Francisco and Winter, Georg E and Fernandez-Carvajal, Asia and Bernardes, Gonçalo J L},
title = {{Selective TRPV2 Antagonists Derived from the Natural Product Piperlongumine Inhibit Cancer Cell Migration and Metastasis}},
journal = {ACS chemical biology},
year = {2026},
month = mar,
volume = {21},
number = {4},
pages = {674--688},
publisher = {American Chemical Society},
issn = {1554-8929},
doi = {10.1021/
url = {https://
pmid = {41879799},
pmcid = {PMC13097083}
}
RIS
TY - JOUR
AU - Kiely-Collins, Hannah
AU - Tang, Cong
AU - Marques, Marta C
AU - Butron, Laura
AU - Lamberti, Angela
AU - Bossons, Nicholas
AU - Offensperger, Fabian
AU - Brennsteiner, Vincenth
AU - Sousa, Bárbara
AU - Carvalho, Luís
AU - Ferrer-Montiel, Antonio
AU - Corzana, Francisco
AU - Winter, Georg E
AU - Fernandez-Carvajal, Asia
AU - Bernardes, Gonçalo J L
TI - Selective TRPV2 Antagonists Derived from the Natural Product Piperlongumine Inhibit Cancer Cell Migration and Metastasis
T2 - ACS chemical biology
J2 - ACS Chem Biol
PY - 2026
DA - 2026/
VL - 21
IS - 4
SP - 674
EP - 688
SN - 1554-8929
PB - American Chemical Society
DO - 10.1021/
UR - https://
LA - en
ER -
CSL-JSON
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