Luke Dow, Professor at Weill Cornell Medicine, shared on LinkedIn:
“This one was a long time coming, but SO glad to see it out!
The work was spearheaded by Jill Zimmerman, with strong structural biology support from Brandon Malone, and a long cast of collaborators including (but not limited to): Kevan Chu, Sher Bahadur, Miguel Foronda Alvaro, Emma Schatoff, Sukanya Goswami, Alyna Katti, Benjamin D. Hopkins, Florencia Madorsky, Tuomas Tammela.
None of it would have been possible without the amazing collaboration from the Tri-I TDI at Weill Cornell Medicine: Shan Sun, Rui Liang, John Ginn, Yoshiyuki Fukase, Efrat Finkin-Groner, Nigel Liverton, David Huggins, FRSC, and Tanweer Khan.
Thank you and congrats to all involved!”
Main preclinical findings on selective TNKS2 inhibitor.
- Identification of a cancer-specific vulnerability: Researchers found that cancers with partial or complete loss of TNKS1, a tankyrase enzyme, become particularly dependent on TNKS2 to maintain WNT/β-catenin signaling, creating a potential therapeutic target.
- Development of a selective TNKS2 inhibitor: Using structure-guided drug design, the team developed a small-molecule inhibitor that suppresses TNKS2 approximately 30 times more strongly than TNKS1, addressing the challenge of distinguishing between these structurally similar enzymes.
- Selective suppression of cancer cell growth: In laboratory experiments, the inhibitor reduced WNT signaling and suppressed the growth of cancer cells with TNKS1 deficiency, while showing no apparent growth-inhibitory effect in cells with normal TNKS1 levels.
- Potential for tumor-restricted treatment: The findings establish a preclinical strategy for exploiting genetic differences between cancer and healthy cells to inhibit WNT signaling while potentially limiting damage to normal tissues. Further optimization and preclinical evaluation are needed before clinical testing.
Title: A selective TNKS2 inhibitor for tumor-restricted WNT suppression
Authors: Jill Zimmerman, Brandon F. Malone, Kevan Chu, Efrat Finkin-Groner, Shan Sun, Rui Liang, Sher Bahadur, Miguel Foronda, Emma M. Schatoff, Elizabeth Granowsky, Florencia Madorsky, Sukanya Goswami, Alyna Katti, Benjamin Leach, Heather Alcorn, Tuomas Tammela, Benjamin Hopkins, Yoshiyuki Fukase, Tanweer Khan, David J. Huggins, John Ginn, Nigel Liverton, Richard K. Hite, Lukas E. Dow
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