A collaborative research team led by Professor Kaori Sakurai at Tokyo University of Agriculture and Technology, together with Associate Professor Hiroaki Itoh and Professor Masayuki Inoue at Graduate School of Pharmaceutical Sciences, the University of Tokyo, has uncovered a previously unknown mechanism of action of yaku’amide B, a structurally complex peptidic natural product derived from deep-sea sponge found in the waters near Yakushima Island, Japan.
Natural products often exhibit multifaceted biological activities due to their structural complexity, interacting transiently with multiple biomolecules. Yaku’amide B was previously shown to inhibit ATP synthase, an essential enzyme for cellular energy production. However, this alone could not fully explain its unique anticancer properties. To address this, the research team employed photoaffinity labeling (PAL), which allows scientists to “capture” molecules that interact briefly with a drug. This work was made available online on January 9, 2026, and published in Volume 148, Issue 3 of the Journal of the American Chemical Society on January 28, 2026.
Associate professor Itoh explains that “using a designed PAL probe, we discovered that yaku’amide B transiently binds to CD9, a membrane protein reported as a cancer stem cell marker. Remarkably, we found that this interaction promotes CD9 degradation inside cancer cells. Concurrently, yaku’amide B moves into mitochondria, where it inhibits ATP synthase, leading to cellular energy depletion.”
Professor Sakurai commented on the significance of the findings:
“CD9 is considered a key marker of aggressive cancer cells, including those responsible for recurrence and metastasis. Discovering that yaku’amide B can induce CD9 degradation is groundbreaking. This finding opens up new possibilities for drug development strategies that target cancer stem cells and their associated pathways.”
Professor Inoue also noted: “ This dual mechanism—ATP depletion and CD9 degradation—provides a compelling explanation for yaku’amide B’s ability to suppress both cancer cell proliferation and migration. Yaku’amide B is the first natural product reported to induce CD9 degradation, highlighting PAL as a powerful strategy for studying transient interactions and paving the way for next-generation anticancer drugs that simultaneously target multiple cellular functions. ”
The study underscores the potential of natural products as starting points for innovative therapeutic approaches, including multi-target drug design and protein degradation strategies, offering new hope for future cancer treatments.
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For more information about Sakurai Research group please visit https://web.tuat.ac.jp/~sakurai/ and Inoue Research Group at https://inoue.f.u-tokyo.ac.jp/
Reference
DOI: https://doi.org/10.1021/jacs.5c13808
About Tokyo University of Agriculture and Technology (TUAT)
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Funding information
This research was financially supported by Grants-in-Aid for Scientific Research (S) (JSPS, JP22H04970) to Masayuki Inoue; the JSPS ACBI program, the Research Grant from the Institute of Global Innovation Research of Tokyo University of Agriculture and Technology (TUAT), and the Kobayashi Foundation to Kaori Sakurai; Grants-in-Aid for Scientific Research (C) (JSPS, JP21K05286 and JP24K08612) and the Transformative Research Area (A) “Latent Chemical Space” (JSPS, JP23H04880 and JP23H04889) to Hiroaki Itoh; Grants-in-Aid for Scientific Research (S) (JSPS, JP21H05037) to Osamu Nureki; fellowships from JSPS (JSPS, JP24KJ0784) and MEXT (WISE Program) to Junhao Fu; and a Nagai Memorial Research Scholarship from the Pharmaceutical Society of Japan and JST SPRING (JPMJSP2108) to Koichi Kamiya. The transcriptome analysis was supported by AdAMS (JSPS, JP22H04922).
Journal of the American Chemical Society
Experimental study
Cells
Photoaffinity Labeling Strategy Reveals Tetraspanin CD9 as a Transient Target of Anticancer Yaku’amide B
28-Jan-2026
The authors declare no competing financial interest.