NU 2020-020
INVENTORS Gary E. Schiltz Daniela E. Matei* Purav Vagadia
SHORT DESCRIPTION A novel series of small molecule inhibitors that suppress metastasis and sensitize cancer cells to standard cytotoxic therapy
BACKGROUND Tissue transglutaminase (TG2) is a multifunctional protein that interacts with fibronectin (FN) and is highly expressed in ovarian tumors at the interface between the cancer cells and the tumor microenvironment. Its functions include stabilizing integrin complexes, which control cell metastasis and cell adhesion to the extracellular matrix, and regulating oncogenic signaling, which drives cancer cell proliferation. Through these mechanisms, ovarian and other cancers can undergo peritoneal metastasis, an advanced stage of cancer that has a poor prognosis and remains a critical unmet medical need. Mechanistic studies on the function and involvement of TG2/FN complexes in physiological processes and disease states have therefore endorsed TG2 as an attractive new target for ovarian cancer to prevent cancer cell-matrix adhesion and peritoneal metastasis.
ABSTRACT Northwestern researchers have developed and synthesized a series of second-generation TG2 inhibitors following high-throughput screening and rational medicinal chemistry optimization of the hit compound. These inhibitors can block TG2 interaction with FN to potently inhibit cancer cell adhesion and decrease oncogenic signaling. In an in vivo model measuring peritoneal metastasis, the synthesized compounds inhibited the adhesion, and therefore metastasis, of ovarian cancer cells to the peritoneum. Pretreatment with one of the optimized inhibitors also sensitized ovarian cancer cells to paclitaxel, a standard chemotherapeutic agent for ovarian cancer. Preliminary studies of this new class of TG2/FN complex inhibitors demonstrate its potentially critical role for anti-metastatic cancer therapy, specifically against peritoneal metastasis. Further optimization of this new class of small molecule inhibitors could produce more potent compounds that block the TG2/FN complex at the interface between cancer cells and the tumor niche.
APPLICATIONS
ADVANTAGES
PUBLICATIONS Sima LE, Yakubov B, Zhang S, Condello S, Grigorescu AA, Nwani NG, Chen L, Schiltz GE, Arvanitis C, Zhang Z, Matei D (2019) Small molecules target the interaction between tissue transglutaminase and fibronectin. Mol. Cancer Ther. 18(6):1057.
IP STATUS A US patent application was filed.
Chemical structures of TG2/FN parent compound and its six derivatives.