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Mol Cancer Ther. 2019 Jun;18(6):1057-1068. doi: 10.1158/1535-7163.MCT-18-1148. Epub 2019 Apr 23.

Small Molecules Target the Interaction between Tissue Transglutaminase and Fibronectin.

Author information

1
Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
2
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
3
Department of Medicinal Chemistry and Molecular Pharmacology and Institute for Drug Discovery, Purdue University, Indiana.
4
Keck Biophysics Facility, Northwestern University, Evanston, Illinois.
5
Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois.
6
Department of Pharmacology, Northwestern University, Chicago, Illinois.
7
Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
8
Center for Advanced Microscopy and Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, Illinosis.
9
Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. daniela.matei@northwestern.edu.
10
Jesse Brown VA Medical Center, Chicago, Illinosis.
#
Contributed equally

Abstract

Tissue transglutaminase (TG2) is a multifunctional protein with enzymatic, GTP-ase, and scaffold properties. TG2 interacts with fibronectin (FN) through its N-terminus domain, stabilizing integrin complexes, which regulate cell adhesion to the matrix. Through this mechanism, TG2 participates in key steps involved in metastasis in ovarian and other cancers. High-throughput screening identified several small molecule inhibitors (SMI) for the TG2/FN complex. Rational medicinal chemistry optimization of the hit compound (TG53) led to second-generation analogues (MT1-6). ELISA demonstrated that these analogues blocked TG2/FN interaction, and bio-layer interferometry (BLI) showed that the SMIs bound to TG2. The compounds also potently inhibited cancer cell adhesion to FN and decreased outside-in signaling mediated through the focal adhesion kinase. Blockade of TG2/FN interaction by the small molecules caused membrane ruffling, delaying the formation of stable focal contacts and mature adhesions points and disrupted organization of the actin cytoskeleton. In an in vivo model measuring intraperitoneal dissemination, MT4 and MT6 inhibited the adhesion of ovarian cancer cells to the peritoneum. Pretreatment with MT4 also sensitized ovarian cancer cells to paclitaxel. The data support continued optimization of the new class of SMIs that block the TG2/FN complex at the interface between cancer cells and the tumor niche.

PMID:
31015308
PMCID:
PMC6548576
[Available on 2020-06-01]
DOI:
10.1158/1535-7163.MCT-18-1148

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