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TitleA potent and selective TNKS2 inhibitor for tumor-selective WNT suppression.
Journal, issue, pagesbioRxiv, Year 2025
Publish dateMar 7, 2025
AuthorsJill Zimmerman / Brandon F Malone / Efrat Finkin-Groner / Shan Sun / Rui Liang / Miguel Foronda / Emma M Schatoff / Elizabeth Granowsky / Sukanya Goswami / Alyna Katti / Benjamin Leach / Heather Alcorn / Tuomas Tammela / Yoshiyuki Fukase / Tanweer Khan / David J Huggins / John Ginn / Nigel Liverton / Richard K Hite / Lukas E Dow /
PubMed AbstractHyperactive 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 ...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.
External linksbioRxiv / PubMed:40093088 / PubMed Central
MethodsEM (single particle) / EM (helical sym.)
Resolution2.19 - 2.52 Å
Structure data

43738

8w23

EMDB-43738, PDB-8w23:
Cryo-EM structure of human tankyrase 2 SAM-PARP filament bound to compound, TDI-2804 (consensus map).
Method: EM (single particle) / Resolution: 2.28 Å

43739

8w25

EMDB-43739, PDB-8w25:
Cryo-EM structure of human tankyrase 2 SAM-PARP filament bound to compound, TDI-2804 (focused refinement map).
Method: EM (helical sym.) / Resolution: 2.42 Å

43740

8w27

EMDB-43740, PDB-8w27:
Cryo-EM structure of human tankyrase 2 SAM-PARP filament bound to compound, XAV (consensus map).
Method: EM (helical sym.) / Resolution: 2.21 Å

43741

8w28

EMDB-43741, PDB-8w28:
Cryo-EM structure of human tankyrase 2 SAM-PARP filament bound to compound, XAV (focused refinement map).
Method: EM (helical sym.) / Resolution: 2.19 Å

43758

8w2t

EMDB-43758, PDB-8w2t:
Cryo-EM structure of human tankyrase 2 SAM-PARP filament - apo state (focused refinement map).
Method: EM (helical sym.) / Resolution: 2.52 Å

43759

8w2u

EMDB-43759, PDB-8w2u:
Cryo-EM structure of human tankyrase 2 SAM-PARP filament -apo state (consensus map).
Method: EM (helical sym.) / Resolution: 2.46 Å

Chemicals

ChemComp-ZN:
Unknown entry

PDB-1ae4:
ALDEHYDE REDUCTASE COMPLEXED WITH COFACTOR AND INHIBITOR, ALPHA CARBON ATOMS ONLY

ChemComp-HOH:
WATER

ChemComp-XAV:
2-[4-(trifluoromethyl)phenyl]-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-ol

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN/INHIBITOR / NAD+ ADP-ribosyltransferase / WNT signaling / inhibitor / SIGNALING PROTEIN / SIGNALING PROTEIN-INHIBITOR complex

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