2. Academic Validation
  3. A potent and selective TNKS2 inhibitor for tumor-selective WNT suppression

A potent and selective TNKS2 inhibitor for tumor-selective WNT suppression

  • bioRxiv. 2025 Mar 7:2025.03.04.641305. doi: 10.1101/2025.03.04.641305.
Jill Zimmerman 1 2,  Brandon F Malone 3,  Efrat Finkin-Groner 4,  Shan Sun 4,  Rui Liang 4,  Miguel Foronda 1,  Emma M Schatoff 1 2,  Elizabeth Granowsky 1,  Sukanya Goswami 1,  Alyna Katti 1 2,  Benjamin Leach 1,  Heather Alcorn 5,  Tuomas Tammela 5,  Yoshiyuki Fukase 4,  Tanweer Khan 4,  David J Huggins 4 6,  John Ginn 4,  Nigel Liverton 4,  Richard K Hite 3,  Lukas E Dow 1 7 8
Affiliations

Affiliations

  • 1 Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, 10021.
  • 2 Graduate School of Medical Sciences, Weill Cornell Medicine, New York, 10065.
  • 3 Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, 10065.
  • 4 Sanders Tri-Institutional Therapeutics Discovery Institute, New York, 10021.
  • 5 Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, 10065.
  • 6 Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10021, USA.
  • 7 Department of Medicine, Weill Cornell Medicine, New York, 10065.
  • 8 Department of Biochemistry, Weill Cornell Medicine, New York, 10065.
PMID: 40093088 DOI: 10.1101/2025.03.04.641305
Abstract

Hyperactive Wnt signaling is a potent Cancer driver, but clinical translation of Wnt inhibitors has been hampered by on-target toxicities. Wnt signaling can be constrained through inhibition of the PARP family Enzymes Tankyrase 1 (TNKS1) and Tankyrase 2 (TNKS2), however, existing TNKS inhibitors suppress Wnt signaling in both tumor and healthy tissues. In this study, we show that the loss of chromosome 8p that occurs in approximately half of advanced epithelial malignancies, creates a collateral vulnerability that enables tumor-selective inhibition of Tankyrase activity. 8p loss depletes expression of TNKS1 and creates a tumor-specific dependency on the functionally redundant TNKS2 protein. Through structure-guided drug design, we identify a first-in-class TNKS2-selective inhibitor that can drive selective Wnt inhibition in TNKS1-deficient oncogenic cell and Organoid models. This work demonstrates a targetable vulnerability in multiple Cancer types, providing a new approach to potent and selective WNT-targeted therapies.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-173349
    TNKS2抑制剂
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z