Small Molecules Target the Interaction between Tissue Transglutaminase and Fibronectin

Area of Science:

• Biochemistry
• Oncology
• Molecular Biology

Background:

• Tissue transglutaminase (TG2) is a multifunctional protein involved in cell adhesion and cancer metastasis.
• TG2 interacts with fibronectin (FN) to stabilize integrin complexes, crucial for cell matrix adhesion.
• Dysregulation of TG2-FN interaction contributes to cancer progression, particularly in ovarian cancer.

Purpose of the Study:

• To identify and optimize small molecule inhibitors (SMIs) targeting the TG2-FN complex.
• To evaluate the efficacy of these SMIs in blocking cancer cell adhesion and metastasis.
• To investigate the downstream effects of TG2-FN blockade on cellular signaling and cytoskeletal organization.

Main Methods:

• High-throughput screening to identify TG2/FN inhibitors.
• Medicinal chemistry optimization of lead compounds (TG53 to MT1-6).
• ELISA and bio-layer interferometry (BLI) to assess inhibitor binding and TG2-FN interaction blockade.
• In vitro assays for cancer cell adhesion and signaling.
• In vivo intraperitoneal dissemination model in mice.

Main Results:

• Second-generation analogues (MT1-6) potently inhibited TG2-FN interaction and bound to TG2.
• SMIs decreased cancer cell adhesion to FN and inhibited outside-in signaling via focal adhesion kinase.
• TG2-FN blockade disrupted actin cytoskeleton organization and focal adhesion formation.
• MT4 and MT6 reduced ovarian cancer cell adhesion in vivo and sensitized cells to paclitaxel.

Conclusions:

• Small molecule inhibitors targeting the TG2-FN interface represent a promising therapeutic strategy for ovarian cancer.
• Blocking TG2-FN interaction disrupts cancer cell adhesion, migration, and metastasis.
• Further optimization of these SMIs could lead to novel treatments for advanced cancers.