Discovery and Characterization of a Small Molecule Inhibitor of the PDZ Domain of Dishevelled

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2009 Apr 23

PMID 19383605

Citations 101

Authors

David Grandy

Jufang Shan

Xinxin Zhang

Sujata Rao

Shailaja Akunuru

Hongyan Li

Yanhui Zhang

Ivan Alpatov

Xin A Zhang

Richard A Lang

De-Li Shi

Jie J Zheng

Affiliations

Soon will be listed here.

Abstract

Dishevelled (Dvl) is an essential protein in the Wnt signaling pathways; it uses its PDZ domain to transduce the Wnt signals from the membrane receptor Frizzled to downstream components. Here, we report identifying a drug-like small molecule compound through structure-based ligand screening and NMR spectroscopy and show the compound to interact at low micromolar affinity with the PDZ domain of Dvl. In a Xenopus testing system, the compound could permeate the cell membrane and block the Wnt signaling pathways. In addition, the compound inhibited Wnt signaling and reduced the levels of apoptosis in the hyaloid vessels of eye. Moreover, this compound also suppressed the growth of prostate cancer PC-3 cells. These biological effects suggest that by blocking the PDZ domain of Dvl, the compound identified in our studies effectively inhibits the Wnt signaling and thus provides a useful tool for studies dissecting the Wnt signaling pathways.

Citing Articles

Wnt Signaling Pathway in Tumor Biology.

Iluta S, Nistor M, Buruiana S, Dima D Genes (Basel). 2025; 15(12.

PMID: 39766864 PMC: 11675244. DOI: 10.3390/genes15121597.

Advances in the development of Wnt/β-catenin signaling inhibitors.

Fujita M, Demizu Y RSC Med Chem. 2024; .

PMID: 39691403 PMC: 11647577. DOI: 10.1039/d4md00749b.

Structural and Functional Insights into Dishevelled-Mediated Wnt Signaling.

Wang L, Zhu R, Wen Z, Fan H, Norwood-Jackson T, Jathan D Cells. 2024; 13(22).

PMID: 39594618 PMC: 11592973. DOI: 10.3390/cells13221870.

Wnt/β-catenin signaling pathway in carcinogenesis and cancer therapy.

Song P, Gao Z, Bao Y, Chen L, Huang Y, Liu Y J Hematol Oncol. 2024; 17(1):46.

PMID: 38886806 PMC: 11184729. DOI: 10.1186/s13045-024-01563-4.

Small-molecule inhibitors of the PDZ domain of Dishevelled proteins interrupt Wnt signalling.

Kamdem N, Roske Y, Kovalskyy D, Platonov M, Balinskyi O, Kreuchwig A Magn Reson (Gott). 2023; 2(1):355-374.

PMID: 37904770 PMC: 10539800. DOI: 10.5194/mr-2-355-2021.

References

Gavrieli Y, Sherman Y, Ben-Sasson S . Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992; 119(3):493-501. PMC: 2289665. DOI: 10.1083/jcb.119.3.493. View

Uematsu K, He B, You L, Xu Z, McCormick F, Jablons D . Activation of the Wnt pathway in non small cell lung cancer: evidence of dishevelled overexpression. Oncogene. 2003; 22(46):7218-21. DOI: 10.1038/sj.onc.1206817. View

Lee H, Wang N, Shao Y, Zheng J . Identification of tripeptides recognized by the PDZ domain of Dishevelled. Bioorg Med Chem. 2009; 17(4):1701-8. PMC: 2713185. DOI: 10.1016/j.bmc.2008.12.060. View

Wallingford J, Habas R . The developmental biology of Dishevelled: an enigmatic protein governing cell fate and cell polarity. Development. 2005; 132(20):4421-36. DOI: 10.1242/dev.02068. View

Jones G, Willett P, Glen R, Leach A, Taylor R . Development and validation of a genetic algorithm for flexible docking. J Mol Biol. 1997; 267(3):727-48. DOI: 10.1006/jmbi.1996.0897. View

Nagahata T, Shimada T, Harada A, Nagai H, Onda M, Yokoyama S . Amplification, up-regulation and over-expression of DVL-1, the human counterpart of the Drosophila disheveled gene, in primary breast cancers. Cancer Sci. 2003; 94(6):515-8. PMC: 11160156. DOI: 10.1111/j.1349-7006.2003.tb01475.x. View

Brannon M, Gomperts M, Sumoy L, Moon R, Kimelman D . A beta-catenin/XTcf-3 complex binds to the siamois promoter to regulate dorsal axis specification in Xenopus. Genes Dev. 1997; 11(18):2359-70. PMC: 316518. DOI: 10.1101/gad.11.18.2359. View

Cheyette B, Waxman J, Miller J, Takemaru K, Sheldahl L, Khlebtsova N . Dapper, a Dishevelled-associated antagonist of beta-catenin and JNK signaling, is required for notochord formation. Dev Cell. 2002; 2(4):449-61. DOI: 10.1016/s1534-5807(02)00140-5. View

Axelrod J, Miller J, Shulman J, Moon R, Perrimon N . Differential recruitment of Dishevelled provides signaling specificity in the planar cell polarity and Wingless signaling pathways. Genes Dev. 1998; 12(16):2610-22. PMC: 317102. DOI: 10.1101/gad.12.16.2610. View

10.

Shan J, Shi D, Wang J, Zheng J . Identification of a specific inhibitor of the dishevelled PDZ domain. Biochemistry. 2005; 44(47):15495-503. DOI: 10.1021/bi0512602. View

11.

Uematsu K, Kanazawa S, You L, He B, Xu Z, Li K . Wnt pathway activation in mesothelioma: evidence of Dishevelled overexpression and transcriptional activity of beta-catenin. Cancer Res. 2003; 63(15):4547-51. View

12.

Kuntz I, Blaney J, Oatley S, LANGRIDGE R, Ferrin T . A geometric approach to macromolecule-ligand interactions. J Mol Biol. 1982; 161(2):269-88. DOI: 10.1016/0022-2836(82)90153-x. View

13.

Wong H, Mao J, Nguyen J, Srinivas S, Zhang W, Liu B . Structural basis of the recognition of the dishevelled DEP domain in the Wnt signaling pathway. Nat Struct Biol. 2000; 7(12):1178-84. PMC: 4381838. DOI: 10.1038/82047. View

14.

Moon R, Kohn A, De Ferrari G, Kaykas A . WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet. 2004; 5(9):691-701. DOI: 10.1038/nrg1427. View

15.

Shan J, Zheng J . Optimizing Dvl PDZ domain inhibitor by exploring chemical space. J Comput Aided Mol Des. 2008; 23(1):37-47. PMC: 2648812. DOI: 10.1007/s10822-008-9236-1. View

16.

Axelrod J . Unipolar membrane association of Dishevelled mediates Frizzled planar cell polarity signaling. Genes Dev. 2001; 15(10):1182-7. PMC: 313798. DOI: 10.1101/gad.890501. View

17.

Giles R, van Es J, Clevers H . Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta. 2003; 1653(1):1-24. DOI: 10.1016/s0304-419x(03)00005-2. View

18.

Shoichet B . Virtual screening of chemical libraries. Nature. 2004; 432(7019):862-5. PMC: 1360234. DOI: 10.1038/nature03197. View

19.

Eldridge M, MURRAY C, Auton T, Paolini G, Mee R . Empirical scoring functions: I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes. J Comput Aided Mol Des. 1997; 11(5):425-45. DOI: 10.1023/a:1007996124545. View

20.

Bohm H . The development of a simple empirical scoring function to estimate the binding constant for a protein-ligand complex of known three-dimensional structure. J Comput Aided Mol Des. 1994; 8(3):243-56. DOI: 10.1007/BF00126743. View